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Cancer Immunology, Immunotherapy : CII logoLink to Cancer Immunology, Immunotherapy : CII
. 2023 Sep 2;72(11):3445–3452. doi: 10.1007/s00262-023-03532-1

Radiation-associated secondary malignancies: a novel opportunity for applying immunotherapies

Tavus Atajanova 1,2,3,#, Md Mahfuzur Rahman 3,#, David J Konieczkowski 4, Zachary S Morris 3,
PMCID: PMC10992240  PMID: 37658906

Abstract

Radiation is commonly used as a treatment intended to cure or palliate cancer patients. Despite remarkable advances in the precision of radiotherapy delivery, even the most advanced forms inevitably expose some healthy tissues surrounding the target site to radiation. On rare occasions, this results in the development of radiation-associated secondary malignancies (RASM). RASM are typically high-grade and carry a poorer prognosis than their non-radiated counterparts. RASM are characterized by a high mutation burden, increased T cell infiltration, and a microenvironment that bears unique inflammatory signatures of prior radiation, including increased expression of various cytokines (e.g., TGF-β, TNF-α, IL4, and IL10). Interestingly, these cytokines have been shown to up-regulate the expression of PD-1 and/or PD-L1—an immune checkpoint receptor/ligand pair that is commonly targeted by immune checkpoint blocking immunotherapies. Here, we review the current understanding of the tumor-immune interactions in RASM, highlight the distinct clinical and molecular characteristics of RASM that may render them immunologically “hot,” and propose a rationale for the formal testing of immune checkpoint blockade as a treatment approach for patients with RASM.

Keywords: Radiation, Secondary malignancies, Cytokines, Immunotherapy

Introduction

Many cancers develop following the stepwise accumulation of mutations. Carcinogens, including ionizing radiation, exert their tumorigenic effect by increasing the rate at which these mutations are acquired. The specific physicochemical characteristics of a carcinogen dictate its interactions with DNA, resulting in mutagen-specific patterns of genomic alterations. Ionizing radiation causes a variety of lesions including single- or double-stranded breaks, single base lesions, and clusters consisting of multiple lesions of potentially different types in close proximity [1].

Over 60% of cancer patients receive radiation during their treatment [2]. Although radiotherapy is highly effective in curing or palliating cancer, it inevitably exposes nearby tissues to radiation. Contemporary approaches have greatly improved the conformality of radiation therapy, thereby reducing this exposure of adjacent healthy tissues and increasing the therapeutic index of the intervention. Nonetheless, irradiation of normal tissue cannot be altogether avoided. In rare cases, this exposure may induce a “secondary” cancer years after the delivery of radiation therapy [35].

With developments in early detection, treatment, and supportive care, the number of long-term cancer survivors has increased. However, it is precisely these long-term survivors who are at higher risk of developing secondary cancers. Approximately 17–19% of cancer patients will go on to develop a second malignancy [6]. Of these, it is estimated that about 8% are RASM [7], being defined as such on the basis of having a different histology than the primary tumor, arising after a latency period of several years after radiation exposure, and occurring within the original therapeutic radiation field [8]. Often high-grade, RASM are associated with poorer prognosis than similar staged tumors that are not associated with radiation [912].

As a result of their relative rarity, the optimal approach to the treatment of RASM has not been defined. With the growing number of cancer patients who receive radiotherapy and the rising number of long-term cancer survivors, it is urgent to advance our understanding of the molecular features of RASM to enable personalized treatment strategies for this challenging group of cancers.

Factors influencing the development of RASM

Patient’s age at radiation

The age of a patient at the time when radiotherapy is received impacts the risk for development of RASM. Childhood cancer survivors are at 3.6–6.4-fold higher risk of developing a second cancer compared to the general population [4, 1315]. Second cancer risk among radiation-exposed childhood cancer survivors in one analysis is 41.3% (95% CI, 37.2–45.4%) at 15 years compared with 25.7% (95% CI, 16.5–34.9%) in non-exposed survivors [16]. The elevated risk of RASM among childhood cancer survivors may reflect several distinct mechanisms: developing tissues may be intrinsically more sensitive to radiation-associated tumorigenesis; the smaller body size of children results in a greater relative percentage of the body exposed to unnecessary radiation; and the long life expectancy of childhood cancer survivors permits more time for secondary malignancies to develop before death from other causes [13, 17]. In support of the latter cause, it has been observed that, even among adult patients, relatively younger age at radiation is associated with increased risk of RASM [18, 19].

Radiation technique and dose–response relationship

Although therapeutic radiation is targeted to areas at risk of tumor spread, adjacent uninvolved areas are inevitably exposed to at least low doses of radiation. The extent of this phenomenon varies by target volume and radiotherapy type. Smaller target volumes, which expose less uninvolved normal tissue to RT, have been associated with lower risk of RASM [2022]. Radiotherapy techniques that decrease normal tissue exposure are also beneficial in this regard and proton therapy, for example, has been shown to result in lower risk of RASM [23, 24]. However, the majority of radiotherapy is delivered with photons (X-rays), which distribute dose along the entire beam path. 3D conformal radiation techniques typically expose a moderate volume of tissue to moderate-to-high doses of radiation. In contrast, newer techniques of intensity modulated radiotherapy (IMRT) or volumetric modulated arc therapy (VMAT) achieve increased conformality of the high-dose radiation area around the intended target volume, but at the cost of an increased volume of tissue exposed to low and potentially still tumorigenic doses of radiation.

The interaction between dose received and RASM development appears complex. At low doses, RASM development has been proposed to be governed by a linear-no-threshold (LNT) model, in which RASM risk is directly proportional to dose. [25]. At higher doses, RASM tumorigenesis is governed by competing interactions between acute cell killing and the risk of late malignant transformation among surviving cells [26]; effects that are modified by both cell-intrinsic and microenvironmental factors [27, 28].

Given the above, concern has been raised that IMRT/VMAT techniques, which increase the volume of tissue receiving low-dose radiation, would increase the risk of RASM compared to 3D conformal techniques [17]. However, large-scale retrospective clinical data has not confirmed such a relationship [23], questioning the putative relationship between low-dose exposure volume and RASM risk. In the context of breast cancer survivors, the risk of secondary cancer was assessed by comparing different treatment plans. Two studies reported that IMRT had a lower risk of secondary cancer compared to three-dimensional conformal radiation therapy (3D-CRT) or VMAT [29, 30]. Given the retrospective and non-randomized approaches to investigating this topic, it remains unclear whether and how photon radiotherapy treatment planning approaches may impact the incidence of RASM and further research is warranted.

Recent proton therapy treatment planning studies have suggested a significantly reduced risk of RASM with passively scattered protons compared to IMRT or 3D-CRT for prostate cancer [31, 32]. Additionally, when comparing IMRT and proton plans, practical estimations suggest lower RASM risk in the proton plan, both in pediatric and older cancer patients [33]. Overall, while the relationship between radiation technique, dose–response, and RASM development is multifaceted, advancements in radiotherapy techniques hold potential for minimizing the risk of RASM. Long-term follow-up and continued research are essential for gaining a comprehensive understanding of this complex relationship.

Genetic susceptibility

Several studies have investigated the interaction between rare, high-penetrance variants and risk of RASM. Li-Fraumeni syndrome (LFS), an autosomal dominant disorder characterized by germline mutations in the p53 tumor suppressor gene, has been associated with up to a 30% rate of second malignancy development following radiotherapy [34], although other studies called into question whether this is actually higher than the background second cancer risk in this histology [35, 36]. Similarly, mutations in the RB1 tumor suppressor gene predispose to RASM [37].

Additional genetic predispositions to RASM include certain single nucleotide polymorphisms (SNPs). In particular, SNPs near PRDM1 are associated with impaired PRDM1 protein expression following radiation exposure and carry a higher risk of RASM in pediatric Hodgkin Lymphoma survivors treated with RT [38]. Additionally, several SNPs on chromosome 5 and 7 are associated with the development of acute myeloid leukemia after treatment with cytotoxic chemotherapy or radiotherapy [39], although the functional significance of these variants remain uncertain.

Other factors

Several additional factors likely modify the risk of RASM. Females have a higher tendency to develop RASM as compared to males [4, 40, 41]. This trend may in part be due to the exposure of breast tissue to radiotherapy for several childhood cancer indications and the subsequently higher risk of this exposed tissue to developing malignancy due to its greater mitotic activity in females versus males. Supporting this notion, length of intact ovarian function following thoracic RT among Hodgkin lymphoma survivors has been associated with risk of radiation-associated breast cancer [22]. Smoking is another critical modifier of RASM risk, suggesting the possibility of a synergistic effect between these two carcinogenic exposures [42, 43].

Characteristics of RASM

RASM can be distinguished from spontaneous tumors based on their histologic, genomic, and molecular characteristics. Whole-genome sequencing of multiple RASM histologies [44] has revealed that RASM exhibit frequent small deletions and balanced inversions, which, unlike radiation-naïve tumors, showed minimal correlation with genomic context. At an expression level, radiation-induced high-grade gliomas manifest greater homogeneity of gene expression and increased expression of ERB3, SOX10, and PDGFRα as compared to patients with de novo gliomas [45]. Targeted investigation of the TP53 locus has identified frequent deletions and recurrent inactivating mutations in radiation-induced sarcomas [46]. In radiation-induced angiosarcomas, array comparative genomic hybridization showed increased rates of MYC amplification compared to primary angiosarcomas [47].

Effects of radiation on the tissue microenvironment of RASM

RASM generally develop after a considerable period of latency. This delay provides time for late effects of radiation to alter the surrounding tissue microenvironment [48], which may contribute to RASM tumorigenesis.

Radiation-induced fibrosis (RIF) is a late radiation toxicity characterized by increased expression of intercellular adhesion molecule 1 (ICAM-1) and platelet endothelial cell adhesion molecule 1 (PECAM-1) [4951]. These endothelial cell adhesion proteins can contribute to the infiltration of neutrophils and other immune cells into tissues [5254]. Contact of neutrophils with collagen fragments and fibronectin in RIF can induce the production of cytokines [55] that create a unique inflammatory environment characterized by increased transforming growth factor β (TGF-β), tumor necrosis factor α (TNF-α), and interleukins (IL-1, IL-4, IL-6, IL-12), and certain other cytokines [5661]. RIF-associated interactions between monocytes and lymphocytes can promote the differentiation of monocytes into macrophages, particularly anti-inflammatory M2 macrophages [62]. These cells secrete platelet-derived growth factors (PDGF), which can lead to increased local production of TGF-β [63], a microenvironmental hallmark of radiation exposure [64, 65].

Once activated, TGFβ functions as an extracellular sensor of oxidative stress and plays an important role in homeostatic growth control [66]. Furthermore, TGFβ is involved in the regulation of tissue responses to damage, an important task that could directly affect tumorigenesis [67, 68]. Increased activation of TGF-β1 is an early occurrence in tissues that have been exposed to both high and low doses of radiation [65, 69, 70] and this may stimulate the differentiation of fibroblasts into myofibroblasts [71]. These myofibroblasts proliferate and secrete excess collagen, fibronectin, and proteoglycans [72], resulting in increased stiffness and thickening of the tissue [64, 73], which is one of the clinical hallmarks of RIF. Over time, excess collagen and endothelial cell damage also reduce vascularity and tissue perfusion, another canonical clinical manifestation of RIF.

The association between radiation-induced fibrosis and radiation-associated secondary malignancies is not fully understood, but some possible mechanisms have been proposed. One mechanism is that radiation-induced fibrosis may create a hypoxic microenvironment that promotes tumor growth and angiogenesis [74]. Another mechanism is that radiation-induced fibrosis may induce chronic inflammation and oxidative stress that cause DNA damage and genomic instability [75]. A third mechanism is that radiation-induced fibrosis may alter the tissue architecture and function, making it more susceptible to malignant transformation [76]. These mechanisms may interact with each other and with other factors to influence the development of second cancers after radiation therapy. Although no study has indicated a direct and causative relationship between RIF and the incidence of RASM, some have suggested a common contributing role for TGF-β1 expression [64, 77, 78].

Moreover, there is currently limited evidence to suggest that treating RIF directly can reduce the risk of RASM. However, it is possible that managing and mitigating the effects of RIF may indirectly contribute to RASM. RIF is associated with chronic inflammation and tissue damage. By effectively managing RIF and minimizing ongoing inflammation, the potential for DNA damage and subsequent malignant transformation may be reduced. RIF results in considerable change in ECM in which RASM primary tumors emerge, specifically the differentiation of fibroblast, secretion of excess collagen, fibronectin, and proteoglycans resulting in increased stiffness and thickening of the tissue [78]. Consequently, these effects of RIF may reduce tissue compliance and may contribute to the level of cancer-associated fibroblasts in secondary malignancies. By altering the microenvironment in which RASM emerges, RIF may alter the ability of a patient’s immune system to mount an effective response against a nascent tumor. It is possible that by affecting immune surveillance and tumor immunoediting, RIF may influence the incidence or the malignant behavior and immunotherapeutic response of RASM tumors. Targeting mechanisms of RIF may present a viable therapeutic strategy for preventing or treating RASM.

Immunogenicity of RASM cancer cells

In contrast to many primary cancers, RASM are characterized by a high mutation burden – particularly balanced inversions and deletions that are 1–100 base pairs in size [44]. Whole-genome sequencing of human osteosarcoma, spindle cell sarcoma, angiosarcoma, and breast cancer revealed greater number of small deletions and enrichment of balanced inversions [44]. Notably, this pattern of mutation creates abundant tumor neoantigens, which may enhance tumor immunogenicity [7982]. While these mutations are random and not uniformly shared across cells in the radiation field, RASM are thought to arise, like other tumors, as an expansion of cells sharing a common progenitor (Fig. 1). This results in a tumor cell population with a high level of shared, tumor-specific mutation-associated neoantigens, which are among the most immunogenic tumor antigens recognized by T cells [83, 84].

Fig. 1.

Fig. 1

Radiation-associated malignancies may exhibit high sensitivity to PD1/PDL-1 inhibition. During radiotherapy, normal tissues are inevitably exposed to ionizing radiation. Years after radiation treatment for the primary tumor, a secondary tumor can arise in the tissues previously exposed to radiation; this radiation-associated secondary tumor has by definition a different histology than the primary tumor. The secondary tumor typically displays a high mutation burden and an increased expression of characteristic cytokines and chemokines, including TGFβ, TNF-α, IL-4, and IL-10. These two factors have been found to be indicative of a higher expression of PD-1/PD-L1 and thus could suggest a therapeutic opportunity for targeting radiation-associated secondary malignancies using immune checkpoint blockade

The unique inflammatory environment of RIF likely drives mechanisms of RASM immune evasion (Fig. 1). For example, the abundant TGF-β1 present in the post-radiation stromal environment increases the expression of the immune checkpoint receptors PD-1 and CTLA-4 on T cells [85]. Likewise, TNF-α, which is frequently expressed in the post-radiation microenvironment, induces stabilization of the immune checkpoint ligand PD-L1 in various types of cancer cells [79, 86]. Specifically, upon binding to TNF receptor on cancer cells, TNF-α induces a signaling cascade that promotes nuclear translocation of NF-κB p65. In the nucleus, p65 binds to and activates the promoter of COPS5, which encodes COP9 signalosome 5 (CSN5). CSN5 can interact with and deubiquitinate PD-L1, leading to protein stabilization and increased surface expression [87]. Wang and colleagues identified TNF-α, IL-17, or a combination of both, as key regulators of PD-L1 expression via activation of NF-κB signaling in human prostate and colon cancer [86]. In renal cell carcinoma, Quandt and colleagues similarly found that IL-4 and TNFα synergistically enhanced the transcription of PD-L1 through direct binding of STAT6 (downstream of IL-4 signaling) and NF-κB (p65, downstream of TNFα) to the PD-L1 promoter [88]. These studies indicate that cytokines upregulated in the setting of RIF, promote the expression of immune checkpoint receptors/ligands on RASM tumor-infiltrating immune cells and tumor cells and this may critically enable immune evasion despite high levels of radiation-induced, tumor-associated neoantigens.

Several prior clinical studies and contemporary understanding of immuno-oncology suggest that a higher tumor mutation burden generally leads to increased endogenous adaptive anti-tumor immunity and higher response rates following immune checkpoint inhibitor therapy. Out of 16 cancer types evaluated in one study, 11 showed a response to anti-PD1 when they had 10 or more mutations per megabase [89]. Response rates varied across different types of cancer, with melanomas having the highest response rates and pancreatic cancer having the lowest [89]. Additionally, mismatch repair-deficient tumors, which have abundant tumor mutations, showed a greater responsiveness to PD-1 blockade compared to mismatch repair-proficient tumors [90]. This has led to the approval of anti-PD-1 therapy for mismatch repair-deficient tumors of any type, including those of the colorectum, uterus, stomach, biliary tract, and pancreas [90, 91]. We now advocate for preclinical and clinical research to investigate the possibility that RASM, as a class of tumors, may similarly exhibit a higher potential for response to anti-PD-1 therapy or to a combination of immune checkpoint inhibitors.

Apart from PD-L1 level, TMB and mismatch repair deficiency others predictive biomarkers for PD-1/PD-L1 include the status of tumor-infiltrating lymphocytes (TIL) [92, 93], immunosuppressive cell populations [93], oncogenic driver mutations [9496], neoantigen repertoire [97], and inflammation-related genes [98, 99]. Because RASM will exhibit differences in each of these parameters relative to non-RASM of the same histological subtype, we hypothesize that immune checkpoint inhibition response will be distinct and potentially greater in patients with RASM and this is presently an unexplored therapeutic opportunity for this very difficult to treat class of malignancies. Evidence is presently too limited to put forth a recommendation for whether or how to apply immunotherapy in RASM. A prospective clinical trial is warranted to evaluate whether this class of tumors can effectively be treated using anti-PD-1 or a combination of immune checkpoint inhibitors.

Conclusions

Many studies have evaluated the potential for radiotherapy to augment response to immunotherapies and enhance patient outcomes when these two modalities are used in conjunction. In contrast, few studies have evaluated the application of immunotherapies specifically for RASM. The growing number of patients who receive radiotherapy and the increasing number of long-term cancer survivors dictate that the rare but grave risk of RASM will be a growing clinical challenge. The high tumor mutation burden and prominent role of chronic inflammation in RIF may present a clinical opportunity to improve the treatment for RASM through targeted immunotherapy approaches. Despite high levels of radiation-induced, tumor-associated neoantigens, RASM tumors may escape eradication through upregulation of immune checkpoint receptors/ligands that result, at least in part, due to effects of chronic inflammation pathways that predominate in the RIF microenvironment in which RASM arise. Targeting these immune checkpoint receptor/ligand interactions and RIF-associated inflammatory pathways is a promising approach that may lead to improved treatment options for RASM (Fig. 1). Such approaches may also enable preventative interventions to reduce the risk of RASM development. Further preclinical and clinical investigation is needed to better define the immunobiology of RASM and to evaluate the potential for shared immunotherapeutic susceptibilities among this collection of cancers that share a common etiology.

Author contributions

T.A., M.R., D.K. and Z.M. conceptualize and wrote the main manuscript text. All authors reviewed the manuscript.

Declarations

Conflict of interest

Z. Morris declares that he is on the Scientific Advisory Board for Archeus Technologies and for Seneca Therapeutics. No disclosures were reported by the other authors.

Footnotes

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Tavus Atajanova and Md Mahfuzur Rahman have contributed equally.

References

  • 1.Ravanat JL, Breton J, Douki T, Gasparutto D, Grand A, Rachidi W, et al. Radiation-mediated formation of complex damage to DNA: a chemical aspect overview. Br J Radiol. 2014;87(1035):20130715. doi: 10.1259/bjr.20130715. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Delaney G, Jacob S, Featherstone C, Barton M. The role of radiotherapy in cancer treatment: estimating optimal utilization from a review of evidence-based clinical guidelines. Cancer. 2005;104(6):1129–1137. doi: 10.1002/cncr.21324. [DOI] [PubMed] [Google Scholar]
  • 3.Clarke M, Collins R, Darby S, Davies C, Elphinstone P, Evans V, et al. Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomised trials. Lancet. 2005;366(9503):2087–2106. doi: 10.1016/S0140-6736(05)67887-7. [DOI] [PubMed] [Google Scholar]
  • 4.Friedman DL, Whitton J, Leisenring W, Mertens AC, Hammond S, Stovall M, et al. Subsequent neoplasms in 5-year survivors of childhood cancer: the childhood cancer survivor study. J Natl Cancer Inst. 2010;102(14):1083–1095. doi: 10.1093/jnci/djq238. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Brenner DJ, Curtis RE, Hall EJ, Ron E. Second malignancies in prostate carcinoma patients after radiotherapy compared with surgery. Cancer. 2000;88(2):398–406. doi: 10.1002/(SICI)1097-0142(20000115)88:2<398::AID-CNCR22>3.0.CO;2-V. [DOI] [PubMed] [Google Scholar]
  • 6.Morton LM, Onel K, Curtis RE, Hungate EA, Armstrong GT. The rising incidence of second cancers: patterns of occurrence and identification of risk factors for children and adults. Am Soc Clin Oncol Edu Book. 2014 doi: 10.14694/EdBook_AM.2014.34.e57. [DOI] [PubMed] [Google Scholar]
  • 7.Berrington de Gonzalez A, Curtis RE, Kry SF, Gilbert E, Lamart S, Berg CD, et al. Proportion of second cancers attributable to radiotherapy treatment in adults: a cohort study in the US SEER cancer registries. Lancet Oncol. 2011;12(4):353–360. doi: 10.1016/S1470-2045(11)70061-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Cahan WG, Woodard HQ, et al. Sarcoma arising in irradiated bone; report of 11 cases. Cancer. 1948;1(1):3–29. doi: 10.1002/1097-0142(194805)1:1<3::AID-CNCR2820010103>3.0.CO;2-7. [DOI] [PubMed] [Google Scholar]
  • 9.Yeang MS, Tay K, Ong WS, Thiagarajan A, Tan DS, Ha TC, et al. Outcomes and prognostic factors of post-irradiation and de novo sarcomas of the head and neck: a histologically matched case-control study. Ann Surg Oncol. 2013;20(9):3066–3075. doi: 10.1245/s10434-013-2979-5. [DOI] [PubMed] [Google Scholar]
  • 10.Gladdy RA, Qin LX, Moraco N, Edgar MA, Antonescu CR, Alektiar KM, et al. Do radiation-associated soft tissue sarcomas have the same prognosis as sporadic soft tissue sarcomas? J Clin Oncol. 2010;28(12):2064–2069. doi: 10.1200/JCO.2009.25.1728. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Bjerkehagen B, Smeland S, Walberg L, Skjeldal S, Hall KS, Nesland JM, et al. Radiation-induced sarcoma: 25-year experience from the Norwegian Radium Hospital. Acta Oncol. 2008;47(8):1475–1482. doi: 10.1080/02841860802047387. [DOI] [PubMed] [Google Scholar]
  • 12.Tay GC, Iyer NG, Ong WS, Tai D, Ang MK, Ha TC, et al. Outcomes and prognostic factors of radiation-induced and de novo head and neck squamous cell carcinomas. Otolaryngol Head Neck Surg. 2016;154(5):880–887. doi: 10.1177/0194599816631726. [DOI] [PubMed] [Google Scholar]
  • 13.Lee JS, DuBois SG, Coccia PF, Bleyer A, Olin RL, Goldsby RE. Increased risk of second malignant neoplasms in adolescents and young adults with cancer. Cancer. 2016;122(1):116–123. doi: 10.1002/cncr.29685. [DOI] [PubMed] [Google Scholar]
  • 14.MacArthur AC, Spinelli JJ, Rogers PC, Goddard KJ, Phillips N, McBride ML. Risk of a second malignant neoplasm among 5-year survivors of cancer in childhood and adolescence in British Columbia. Canada Pediatr Blood Cancer. 2007;48(4):453–459. doi: 10.1002/pbc.20921. [DOI] [PubMed] [Google Scholar]
  • 15.Meadows AT, Friedman DL, Neglia JP, Mertens AC, Donaldson SS, Stovall M, et al. Second neoplasms in survivors of childhood cancer: findings from the childhood cancer survivor study cohort. J Clin Oncol. 2009;27(14):2356–2362. doi: 10.1200/JCO.2008.21.1920. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Armstrong GT, Liu W, Leisenring W, Yasui Y, Hammond S, Bhatia S, et al. Occurrence of multiple subsequent neoplasms in long-term survivors of childhood cancer: a report from the childhood cancer survivor study. J Clin Oncol. 2011;29(22):3056–3064. doi: 10.1200/JCO.2011.34.6585. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Hall EJ. Intensity-modulated radiation therapy, protons, and the risk of second cancers. Int J Radiat Oncol Biol Phys. 2006;65(1):1–7. doi: 10.1016/j.ijrobp.2006.01.027. [DOI] [PubMed] [Google Scholar]
  • 18.Boice JD, Jr, Harvey EB, Blettner M, Stovall M, Flannery JT. Cancer in the contralateral breast after radiotherapy for breast cancer. N Engl J Med. 1992;326(12):781–785. doi: 10.1056/NEJM199203193261201. [DOI] [PubMed] [Google Scholar]
  • 19.Chaturvedi AK, Engels EA, Gilbert ES, Chen BE, Storm H, Lynch CF, et al. Second cancers among 104,760 survivors of cervical cancer: evaluation of long-term risk. J Natl Cancer Inst. 2007;99(21):1634–1643. doi: 10.1093/jnci/djm201. [DOI] [PubMed] [Google Scholar]
  • 20.Berrington de Gonzalez A, Wong J, Kleinerman R, Kim C, Morton L, Bekelman JE. Risk of second cancers according to radiation therapy technique and modality in prostate cancer survivors. Int J Radiat Oncol Biol Phys. 2015;91(2):295–302. doi: 10.1016/j.ijrobp.2014.10.040. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Hooning MJ, Aleman BM, Hauptmann M, Baaijens MH, Klijn JG, Noyon R, et al. Roles of radiotherapy and chemotherapy in the development of contralateral breast cancer. J Clin Oncol. 2008;26(34):5561–5568. doi: 10.1200/JCO.2007.16.0192. [DOI] [PubMed] [Google Scholar]
  • 22.De Bruin ML, Sparidans J, vanʹt Veer MB, Noordijk EM, Louwman MW, Zijlstra JM, et al. Breast cancer risk in female survivors of Hodgkin's lymphoma: lower risk after smaller radiation volumes. J Clin Oncol. 2009;27(26):4239–4246. doi: 10.1200/JCO.2008.19.9174. [DOI] [PubMed] [Google Scholar]
  • 23.Xiang M, Chang DT, Pollom EL. Second cancer risk after primary cancer treatment with three-dimensional conformal, intensity-modulated, or proton beam radiation therapy. Cancer. 2020;126(15):3560–3568. doi: 10.1002/cncr.32938. [DOI] [PubMed] [Google Scholar]
  • 24.Sethi RV, Shih HA, Yeap BY, Mouw KW, Petersen R, Kim DY, et al. Second nonocular tumors among survivors of retinoblastoma treated with contemporary photon and proton radiotherapy. Cancer. 2014;120(1):126–133. doi: 10.1002/cncr.28387. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.Mullenders L, Atkinson M, Paretzke H, Sabatier L, Bouffler S. Assessing cancer risks of low-dose radiation. Nat Rev Cancer. 2009;9(8):596–604. doi: 10.1038/nrc2677. [DOI] [PubMed] [Google Scholar]
  • 26.Schneider U, Lomax A, Timmermann B. Second cancers in children treated with modern radiotherapy techniques. Radiother Oncol. 2008;89(2):135–140. doi: 10.1016/j.radonc.2008.07.017. [DOI] [PubMed] [Google Scholar]
  • 27.Coussens LM, Werb Z. Inflammation and cancer. Nature. 2002;420(6917):860–867. doi: 10.1038/nature01322. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Ikushima H, Miyazono K. TGFbeta signalling: a complex web in cancer progression. Nat Rev Cancer. 2010;10(6):415–424. doi: 10.1038/nrc2853. [DOI] [PubMed] [Google Scholar]
  • 29.Zhang Q, Liu J, Ao N, Yu H, Peng Y, Ou L, et al. Secondary cancer risk after radiation therapy for breast cancer with different radiotherapy techniques. Sci Rep. 2020;10(1):1220. doi: 10.1038/s41598-020-58134-z. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.Abo-Madyan Y, Aziz MH, Aly MM, Schneider F, Sperk E, Clausen S, et al. Second cancer risk after 3D-CRT, IMRT and VMAT for breast cancer. Radiother Oncol. 2014;110(3):471–476. doi: 10.1016/j.radonc.2013.12.002. [DOI] [PubMed] [Google Scholar]
  • 31.Chera BS, Vargas C, Morris CG, Louis D, Flampouri S, Yeung D, et al. Dosimetric study of pelvic proton radiotherapy for high-risk prostate cancer. Int J Radiat Oncol Biol Phys. 2009;75(4):994–1002. doi: 10.1016/j.ijrobp.2009.01.044. [DOI] [PubMed] [Google Scholar]
  • 32.Fontenot JD, Lee AK, Newhauser WD. Risk of secondary malignant neoplasms from proton therapy and intensity-modulated x-ray therapy for early-stage prostate cancer. Int J Radiat Oncol Biol Phys. 2009;74(2):616–622. doi: 10.1016/j.ijrobp.2009.01.001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33.Braunstein S, Nakamura JL. Radiotherapy-induced malignancies: review of clinical features, pathobiology, and evolving approaches for mitigating risk. Front Oncol. 2013;3:73. doi: 10.3389/fonc.2013.00073. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.Bougeard G, Renaux-Petel M, Flaman JM, Charbonnier C, Fermey P, Belotti M, et al. Revisiting li-fraumeni syndrome from TP53 mutation carriers. J Clin Oncol. 2015;33(21):2345–2352. doi: 10.1200/JCO.2014.59.5728. [DOI] [PubMed] [Google Scholar]
  • 35.Le AN, Harton J, Desai H, Powers J, Zelley K, Bradbury AR, et al. Frequency of radiation-induced malignancies post-adjuvant radiotherapy for breast cancer in patients with Li-Fraumeni syndrome. Breast Cancer Res Treat. 2020;181(1):181–188. doi: 10.1007/s10549-020-05612-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.Hendrickson PG, Luo Y, Kohlmann W, Schiffman J, Maese L, Bishop AJ, et al. Radiation therapy and secondary malignancy in Li-Fraumeni syndrome: a hereditary cancer registry study. Cancer Med. 2020;9(21):7954–7963. doi: 10.1002/cam4.3427. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37.Wong FL, Boice JD, Jr, Abramson DH, Tarone RE, Kleinerman RA, Stovall M, et al. Cancer incidence after retinoblastoma. Radiat Sarcoma Risk JAMA. 1997;278(15):1262–1267. doi: 10.1001/jama.278.15.1262. [DOI] [PubMed] [Google Scholar]
  • 38.Best T, Li D, Skol AD, Kirchhoff T, Jackson SA, Yasui Y, et al. Variants at 6q21 implicate PRDM1 in the etiology of therapy-induced second malignancies after Hodgkin's lymphoma. Nat Med. 2011;17(8):941–943. doi: 10.1038/nm.2407. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 39.Knight JA, Skol AD, Shinde A, Hastings D, Walgren RA, Shao J, et al. Genome-wide association study to identify novel loci associated with therapy-related myeloid leukemia susceptibility. Blood. 2009;113(22):5575–5582. doi: 10.1182/blood-2008-10-183244. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40.Armstrong GT, Sklar CA, Hudson MM, Robison LL. Long-term health status among survivors of childhood cancer: Does sex matter? J Clin Oncol. 2007;25(28):4477–4489. doi: 10.1200/JCO.2007.11.2003. [DOI] [PubMed] [Google Scholar]
  • 41.Bhatia S, Sklar C. Second cancers in survivors of childhood cancer. Nat Rev Cancer. 2002;2(2):124–132. doi: 10.1038/nrc722. [DOI] [PubMed] [Google Scholar]
  • 42.Prochazka M, Hall P, Gagliardi G, Granath F, Nilsson BN, Shields PG, et al. Ionizing radiation and tobacco use increases the risk of a subsequent lung carcinoma in women with breast cancer: case-only design. J Clin Oncol. 2005;23(30):7467–7474. doi: 10.1200/JCO.2005.01.7335. [DOI] [PubMed] [Google Scholar]
  • 43.Travis LB, Gospodarowicz M, Curtis RE, Clarke EA, Andersson M, Glimelius B, et al. Lung cancer following chemotherapy and radiotherapy for Hodgkin's disease. J Natl Cancer Inst. 2002;94(3):182–192. doi: 10.1093/jnci/94.3.182. [DOI] [PubMed] [Google Scholar]
  • 44.Behjati S, Gundem G, Wedge DC, Roberts ND, Tarpey PS, Cooke SL, et al. Mutational signatures of ionizing radiation in second malignancies. Nat Commun. 2016;7:12605. doi: 10.1038/ncomms12605. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 45.Donson AM, Erwin NS, Kleinschmidt-DeMasters BK, Madden JR, Addo-Yobo SO, Foreman NK. Unique molecular characteristics of radiation-induced glioblastoma. J Neuropathol Exp Neurol. 2007;66(8):740–749. doi: 10.1097/nen.0b013e3181257190. [DOI] [PubMed] [Google Scholar]
  • 46.Gonin-Laurent N, Gibaud A, Huygue M, Lefevre SH, Le Bras M, Chauveinc L, et al. Specific TP53 mutation pattern in radiation-induced sarcomas. Carcinogenesis. 2006;27(6):1266–1272. doi: 10.1093/carcin/bgi356. [DOI] [PubMed] [Google Scholar]
  • 47.Manner J, Radlwimmer B, Hohenberger P, Mossinger K, Kuffer S, Sauer C, et al. MYC high level gene amplification is a distinctive feature of angiosarcomas after irradiation or chronic lymphedema. Am J Pathol. 2010;176(1):34–39. doi: 10.2353/ajpath.2010.090637. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 48.Nguyen DH, Oketch-Rabah HA, Illa-Bochaca I, Geyer FC, Reis-Filho JS, Mao JH, et al. Radiation acts on the microenvironment to affect breast carcinogenesis by distinct mechanisms that decrease cancer latency and affect tumor type. Cancer Cell. 2011;19(5):640–651. doi: 10.1016/j.ccr.2011.03.011. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 49.Olschowka JA, Kyrkanides S, Harvey BK, O'Banion MK, Williams JP, Rubin P, et al. ICAM-1 induction in the mouse CNS following irradiation. Brain Behav Immun. 1997;11(4):273–285. doi: 10.1006/brbi.1997.0506. [DOI] [PubMed] [Google Scholar]
  • 50.Zhao Y, Zhang T, Wang Y, Lu D, Du J, Feng X, et al. ICAM-1 orchestrates the abscopal effect of tumor radiotherapy. Proc Natl Acad Sci. 2021;118(14):e2010333118. doi: 10.1073/pnas.2010333118. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 51.Chen B, Zhao Z, Lee V, Reddy R, Stoodley M. Radiation-induced expression of platelet endothelial cell adhesion molecule-1 in cerebral endothelial cells. Int J Radiat Res. 2016;14(3):181–188. doi: 10.18869/acadpub.ijrr.14.3.181. [DOI] [Google Scholar]
  • 52.Sans E, Delachanal E, Duperray A. Analysis of the roles of ICAM-1 in neutrophil transmigration using a reconstituted mammalian cell expression model: implication of ICAM-1 cytoplasmic domain and Rho-dependent signaling pathway. J Immunol. 2001;166(1):544–551. doi: 10.4049/jimmunol.166.1.544. [DOI] [PubMed] [Google Scholar]
  • 53.Williams MR, Luscinskas FW. Leukocyte rolling and adhesion via ICAM-1 signals to endothelial permeability. Focus on "Leukocyte rolling and adhesion both contribute to regulation of microvascular permeability to albumin via ligation of ICAM-1". Am J Physiol Cell Physiol. 2011;301(4):777–779. doi: 10.1152/ajpcell.00250.2011. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 54.Grönloh MLB, Arts JJG, Martínez SP, van der Veen AA, Kempers L, van Steen ACI, et al. Endothelial transmigration hotspots limit vascular leakage through heterogeneous expression of ICAM1. bioRxiv. 2022:2022.01.14.476297 [DOI] [PMC free article] [PubMed]
  • 55.Padmanabhan J, Gonzalez AL. The effects of extracellular matrix proteins on neutrophil-endothelial interaction–a roadway to multiple therapeutic opportunities. Yale J Biol Med. 2012;85(2):167–185. [PMC free article] [PubMed] [Google Scholar]
  • 56.Calveley VL, Khan MA, Yeung IW, Vandyk J, Hill RP. Partial volume rat lung irradiation: temporal fluctuations of in-field and out-of-field DNA damage and inflammatory cytokines following irradiation. Int J Radiat Biol. 2005;81(12):887–899. doi: 10.1080/09553000600568002. [DOI] [PubMed] [Google Scholar]
  • 57.Finkelstein JN, Johnston C, Barrett T, Oberdorster G. Particulate-cell interactions and pulmonary cytokine expression. Environ Health Perspect. 1997;105(Suppl 5):1179–1182. doi: 10.1289/ehp.97105s51179. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 58.Olman MA, White KE, Ware LB, Cross MT, Zhu S, Matthay MA. Microarray analysis indicates that pulmonary edema fluid from patients with acute lung injury mediates inflammation, mitogen gene expression, and fibroblast proliferation through bioactive interleukin-1. Chest. 2002;121(3 Suppl):69S–70S. doi: 10.1378/chest.121.3_suppl.69S. [DOI] [PubMed] [Google Scholar]
  • 59.Porter DW, Ye J, Ma J, Barger M, Robinson VA, Ramsey D, et al. Time course of pulmonary response of rats to inhalation of crystalline silica: NF-kappa B activation, inflammation, cytokine production, and damage. Inhal Toxicol. 2002;14(4):349–367. doi: 10.1080/08958370252870998. [DOI] [PubMed] [Google Scholar]
  • 60.Sedgwick JB, Menon I, Gern JE, Busse WW. Effects of inflammatory cytokines on the permeability of human lung microvascular endothelial cell monolayers and differential eosinophil transmigration. J Allergy Clin Immunol. 2002;110(5):752–756. doi: 10.1067/mai.2002.128581. [DOI] [PubMed] [Google Scholar]
  • 61.Di Maggio FM, Minafra L, Forte GI, Cammarata FP, Lio D, Messa C, et al. Portrait of inflammatory response to ionizing radiation treatment. J Inflamm (Lond) 2015;12:14. doi: 10.1186/s12950-015-0058-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 62.Gordon S, Martinez FO. Alternative activation of macrophages: mechanism and functions. Immunity. 2010;32(5):593–604. doi: 10.1016/j.immuni.2010.05.007. [DOI] [PubMed] [Google Scholar]
  • 63.Li MO, Wan YY, Sanjabi S, Robertson AK, Flavell RA. Transforming growth factor-beta regulation of immune responses. Annu Rev Immunol. 2006;24:99–146. doi: 10.1146/annurev.immunol.24.021605.090737. [DOI] [PubMed] [Google Scholar]
  • 64.Martin M, Lefaix J, Delanian S. TGF-beta1 and radiation fibrosis: a master switch and a specific therapeutic target? Int J Radiat Oncol Biol Phys. 2000;47(2):277–290. doi: 10.1016/S0360-3016(00)00435-1. [DOI] [PubMed] [Google Scholar]
  • 65.Anscher MS, Crocker IR, Jirtle RL. Transforming growth factor-beta 1 expression in irradiated liver. Radiat Res. 1990;122(1):77–85. doi: 10.2307/3577586. [DOI] [PubMed] [Google Scholar]
  • 66.Barcellos-Hoff MH, Dix TA. Redox-mediated activation of latent transforming growth factor-beta 1. Mol Endocrinol. 1996;10(9):1077–1083. doi: 10.1210/mend.10.9.8885242. [DOI] [PubMed] [Google Scholar]
  • 67.Barcellos-Hoff MH, Park C, Wright EG. Radiation and the microenvironment-tumorigenesis and therapy. Nat Rev Cancer. 2005;5(11):867–875. doi: 10.1038/nrc1735. [DOI] [PubMed] [Google Scholar]
  • 68.Bhowmick NA, Chytil A, Plieth D, Gorska AE, Dumont N, Shappell S, et al. TGF-beta signaling in fibroblasts modulates the oncogenic potential of adjacent epithelia. Science. 2004;303(5659):848–851. doi: 10.1126/science.1090922. [DOI] [PubMed] [Google Scholar]
  • 69.Barcellos-Hoff MH, Derynck R, Tsang ML, Weatherbee JA. Transforming growth factor-beta activation in irradiated murine mammary gland. J Clin Invest. 1994;93(2):892–899. doi: 10.1172/JCI117045. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 70.Wang J, Zheng H, Sung CC, Richter KK, Hauer-Jensen M. Cellular sources of transforming growth factor-beta isoforms in early and chronic radiation enteropathy. Am J Pathol. 1998;153(5):1531–1540. doi: 10.1016/S0002-9440(10)65741-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 71.Yarnold J, Brotons MC. Pathogenetic mechanisms in radiation fibrosis. Radiother Oncol. 2010;97(1):149–161. doi: 10.1016/j.radonc.2010.09.002. [DOI] [PubMed] [Google Scholar]
  • 72.Chithra P, Sajithlal GB, Chandrakasan G. Influence of Aloe vera on the glycosaminoglycans in the matrix of healing dermal wounds in rats. J Ethnopharmacol. 1998;59(3):179–186. doi: 10.1016/S0378-8741(97)00112-8. [DOI] [PubMed] [Google Scholar]
  • 73.Lefaix JL, Daburon F. Diagnosis of acute localized irradiation lesions: review of the French experimental experience. Health Phys. 1998;75(4):375–384. doi: 10.1097/00004032-199810000-00003. [DOI] [PubMed] [Google Scholar]
  • 74.Dracham CB, Shankar A, Madan R. Radiation induced secondary malignancies: a review article. Radiat Oncol J. 2018;36(2):85–94. doi: 10.3857/roj.2018.00290. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 75.Khanna L, Prasad SR, Yedururi S, Parameswaran AM, Marcal LP, Sandrasegaran K, et al. Second malignancies after radiation therapy: update on pathogenesis and cross-sectional imaging findings. Radiographics. 2021;41(3):876–894. doi: 10.1148/rg.2021200171. [DOI] [PubMed] [Google Scholar]
  • 76.Nepon H, Safran T, Reece EM, Murphy AM, Vorstenbosch J, Davison PG. Radiation-induced tissue damage: clinical consequences and current treatment options. Semin Plast Surg. 2021;35(3):181–188. doi: 10.1055/s-0041-1731464. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 77.Sahai E, Astsaturov I, Cukierman E, DeNardo DG, Egeblad M, Evans RM, et al. A framework for advancing our understanding of cancer-associated fibroblasts. Nat Rev Cancer. 2020;20(3):174–186. doi: 10.1038/s41568-019-0238-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 78.Ejaz A, Greenberger JS, Rubin PJ. Understanding the mechanism of radiation induced fibrosis and therapy options. Pharmacol Ther. 2019;204:107399. doi: 10.1016/j.pharmthera.2019.107399. [DOI] [PubMed] [Google Scholar]
  • 79.Yu G, Pang Y, Merchant M, Kesserwan C, Gangalapudi V, Abdelmaksoud A, et al. Tumor mutation burden, expressed neoantigens and the immune microenvironment in diffuse gliomas. Cancers (Basel). 2021;13(23):6092. doi: 10.3390/cancers13236092. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 80.Kocakavuk E, Anderson KJ, Varn FS, Johnson KC, Amin SB, Sulman EP, et al. Radiotherapy is associated with a deletion signature that contributes to poor outcomes in patients with cancer. Nat Genet. 2021;53(7):1088–1096. doi: 10.1038/s41588-021-00874-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 81.Wang P, Chen Y, Wang C. Beyond tumor mutation burden: tumor neoantigen burden as a biomarker for immunotherapy and other types of therapy. Front Oncol. 2021;11:672677. doi: 10.3389/fonc.2021.672677. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 82.Lhuillier C, Rudqvist NP, Elemento O, Formenti SC, Demaria S. Radiation therapy and anti-tumor immunity: exposing immunogenic mutations to the immune system. Genome Med. 2019;11(1):40. doi: 10.1186/s13073-019-0653-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 83.O'Sullivan T, Saddawi-Konefka R, Vermi W, Koebel CM, Arthur C, White JM, et al. Cancer immunoediting by the innate immune system in the absence of adaptive immunity. J Exp Med. 2012;209(10):1869–1882. doi: 10.1084/jem.20112738. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 84.Matsushita H, Vesely MD, Koboldt DC, Rickert CG, Uppaluri R, Magrini VJ, et al. Cancer exome analysis reveals a T-cell-dependent mechanism of cancer immunoediting. Nature. 2012;482(7385):400–404. doi: 10.1038/nature10755. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 85.Bao S, Jiang X, Jin S, Tu P, Lu J. TGF-beta1 induces immune escape by enhancing PD-1 and CTLA-4 expression on T lymphocytes in hepatocellular carcinoma. Front Oncol. 2021;11:694145. doi: 10.3389/fonc.2021.694145. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 86.Wang X, Yang L, Huang F, Zhang Q, Liu S, Ma L, et al. Inflammatory cytokines IL-17 and TNF-alpha up-regulate PD-L1 expression in human prostate and colon cancer cells. Immunol Lett. 2017;184:7–14. doi: 10.1016/j.imlet.2017.02.006. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 87.Lim SO, Li CW, Xia W, Cha JH, Chan LC, Wu Y, et al. Deubiquitination and stabilization of PD-L1 by CSN5. Cancer Cell. 2016;30(6):925–939. doi: 10.1016/j.ccell.2016.10.010. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 88.Quandt D, Jasinski-Bergner S, Muller U, Schulze B, Seliger B. Synergistic effects of IL-4 and TNFalpha on the induction of B7–H1 in renal cell carcinoma cells inhibiting allogeneic T cell proliferation. J Transl Med. 2014;12:151. doi: 10.1186/1479-5876-12-151. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 89.Valero C, Lee M, Hoen D, Zehir A, Berger MF, Seshan VE, et al. Response rates to Anti-PD-1 immunotherapy in microsatellite-stable solid tumors with 10 or more mutations per megabase. JAMA Oncol. 2021;7(5):739–743. doi: 10.1001/jamaoncol.2020.7684. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 90.Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015;372(26):2509–2520. doi: 10.1056/NEJMoa1500596. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 91.Cercek A, Lumish M, Sinopoli J, Weiss J, Shia J, Lamendola-Essel M, et al. PD-1 blockade in mismatch repair-deficient, locally advanced rectal cancer. N Engl J Med. 2022;386(25):2363–2376. doi: 10.1056/NEJMoa2201445. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 92.Solomon B, Young RJ, Bressel M, Urban D, Hendry S, Thai A, et al. Prognostic significance of PD-L1(+) and CD8(+) immune cells in HPV(+) oropharyngeal squamous cell carcinoma. Cancer Immunol Res. 2018;6(3):295–304. doi: 10.1158/2326-6066.CIR-17-0299. [DOI] [PubMed] [Google Scholar]
  • 93.Briere D, Sudhakar N, Woods DM, Hallin J, Engstrom LD, Aranda R, et al. The class I/IV HDAC inhibitor mocetinostat increases tumor antigen presentation, decreases immune suppressive cell types and augments checkpoint inhibitor therapy. Cancer Immunol Immunother. 2018;67(3):381–392. doi: 10.1007/s00262-017-2091-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 94.Liu C, Zheng S, Jin R, Wang X, Wang F, Zang R, et al. The superior efficacy of anti-PD-1/PD-L1 immunotherapy in KRAS-mutant non-small cell lung cancer that correlates with an inflammatory phenotype and increased immunogenicity. Cancer Lett. 2020;470:95–105. doi: 10.1016/j.canlet.2019.10.027. [DOI] [PubMed] [Google Scholar]
  • 95.Hastings K, Yu HA, Wei W, Sanchez-Vega F, DeVeaux M, Choi J, et al. EGFR mutation subtypes and response to immune checkpoint blockade treatment in non-small-cell lung cancer. Ann Oncol. 2019;30(8):1311–1320. doi: 10.1093/annonc/mdz141. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 96.Biton J, Mansuet-Lupo A, Pecuchet N, Alifano M, Ouakrim H, Arrondeau J, et al. TP53, STK11, and EGFR mutations predict tumor immune profile and the response to Anti-PD-1 in lung adenocarcinoma. Clin Cancer Res. 2018;24(22):5710–5723. doi: 10.1158/1078-0432.CCR-18-0163. [DOI] [PubMed] [Google Scholar]
  • 97.Yi M, Qin S, Zhao W, Yu S, Chu Q, Wu K. The role of neoantigen in immune checkpoint blockade therapy. Exp Hematol Oncol. 2018;7:28. doi: 10.1186/s40164-018-0120-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 98.Yi M, Li A, Zhou L, Chu Q, Luo S, Wu K. Immune signature-based risk stratification and prediction of immune checkpoint inhibitor's efficacy for lung adenocarcinoma. Cancer Immunol Immunother. 2021;70(6):1705–1719. doi: 10.1007/s00262-020-02817-z. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 99.Thompson JC, Hwang WT, Davis C, Deshpande C, Jeffries S, Rajpurohit Y, et al. Gene signatures of tumor inflammation and epithelial-to-mesenchymal transition (EMT) predict responses to immune checkpoint blockade in lung cancer with high accuracy. Lung Cancer. 2020;139:1–8. doi: 10.1016/j.lungcan.2019.10.012. [DOI] [PMC free article] [PubMed] [Google Scholar]

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