Cancer immunity and immunotherapy beyond COVID-19

Introduction

The COVID-19 pandemic has forced all of us to change priorities and perspectives. The reaction of the scientific community has been focused, fast and incredibly effective. It is difficult to recall in the history of mankind such a cohesion of intents and efforts among countries in defeating a new threat to humanity. We have learned that joining forces is the winning strategy against any threat, cancer included. However, SARS-CoV-2 only partially distracted the basic, translational, and clinical research in cancer.

Inspired by this overwhelming experience and eager to share the last groundbreaking discoveries in cancer immunology and immunotherapy with the scientific community and for the benefit of cancer patients, the Italian Network for the Biotherapy of Cancer (NIBT) organized the XIX NIBIT Meeting 2021, whose main theme was “Cancer immunity and immunotherapy beyond the COVID-19 pandemic.” The meeting rolled out in the web on October 14–15, 2021, and gathered top clinicians and scientists to discuss about novel concepts in cancer immunology, such as trained immunity and cancer & immune metabolism. Almost 200 delegates were updated on cutting-hedge therapies in hematologic malignancies and solid tumors including melanoma, lung, breast, prostate, head and neck and several others. Each session hosted a 20’ open discussion animated by experts in the field. There was plenty of space for oral communications from the youngest investigators. Three poster sessions in the morning allowed 20 investigators to orally present their most recent and exciting findings (Supplementary Fig. S1). Thus, NIBIT was proud to meet the educational needs of its members and of young investigators committed to cancer immunotherapy.

Session 1. What’s new in cancer immunotherapy

The XIX NIBIT meeting began with a session focused on novelties in clinical cancer immunotherapy. This session was jointly organized by the NIBIT and the Associazione Italiana di Oncologia Medica (AIOM), and witnessed Rita Chiari (Padova, Italy), Lucia Del Mastro (Genova, Italy), Wolf-Herman Fridman (Paris, France) and Paolo Ascierto (Napoli, Italy) as discussants.

Since the FDA approval of Ipilimumab in 2011, several immune checkpoint inhibitors (ICIs) have been added to the therapeutic arsenal against cancer [1]. These agents, in several cases, allow durable responses with acceptable safety and are now approved for the treatment of various types of malignancy. However, a relevant percentage of cancer patients still do not benefit from ICI treatment [1]. Therefore, preclinical and clinical research are focused on how to improve the outcome of non-responders. Within this vein, Alexander Eggermont (Utrecht, The Netherlands) discussed about recent advancements in the use ICI for melanoma patients. Whereas adjuvant therapy is currently applied to patients with stage III or IIB/C melanoma, most melanoma patients are diagnosed at stage I/IIA. Despite an excellent prognosis, and a 10-year survival rate higher than 90%, stage I/IIA melanomas account for more than a half of future melanoma-related deaths [2, 3]. Therefore, an unmet clinical need is to identify patients who will more likely relapse after surgery. The CP-GEP model combines patient age, Breslow thickness and gene expression profile of melanoma biopsy. The resulting score may improve the detection of melanoma patients that could avoid sentinel lymph node biopsy because of their low risk of nodal metastasis. The same model can be used to identify stage I/IIA patients who are at high risk of disease relapse and support clinical decision-making on adjuvant therapy [4]. Similarly, in the ongoing NivoMela trial (NCT04309409) stage II melanoma patients are screened by the MelaGenix GEP score to identify subjects at high risk of relapse, and patients are eventually randomized to receive either nivolumab as adjuvant treatment or observation only.

In the neoadjuvant setting, data from the OpACIN-neo trial (NCT02977052), after a median follow-up of 24.6 months, showed a high rate of pathologic response and only the 2% within this group of patients relapsed. The PRADO trial (NCT02977052), an extension cohort of the OpACIN-neo study, aims at assessing personalized response-driven adjuvant therapy. In this trial, lymph node dissection was omitted in 59 (60%) patients, the consequences were fewer surgery-related adverse events and higher quality of life scores. The ongoing NADINA trial (NCT04949113) will further clarify the role of lymph node dissection in the neoadjuvant era.

Adoptive T cell therapy (ACT) is one of the most promising innovative approaches among cancer treatments. Chiara Bonini (Milan, Italy) explored the major challenges of this area of research. CD44v6 emerged as a new target, expressed in acute myeloid leukemia (AML) and multiple myeloma (MM) and associates with poor prognosis [5]. A clinical trial to assess safety, antitumor activity, and feasibility of CD44v6 CAR T cell immunotherapy in AML and MM is currently ongoing (NCT04097301). One way to improve ACT efficacy, that showed promising results, consists in enabling T cells to fight the immunosuppressive tumor microenvironment [6] by editing endogenous TCR genes and inhibitory receptor genes [7].

Federico Cappuzzo (Rome, Italy) presented an impressive overview on progresses in non-small cell lung cancer (NSCLC) treatment. In the adjuvant setting, the data of Impower010, which evaluated Atezolizumab after surgery, have demonstrated a significant impact over disease free survival (DFS) [8]. In the locally advanced setting, the COAST trial (NCT03822351) investigated the addition of Oleclumab or Monalizumab to Durvalumab with interesting results. In the metastatic disease, data from EMPOWER-Lung 3 may add Cemiplimab among the therapeutic arsenal for PD-L1 negative NSCLC patients [9]. Moreover, in first line for advanced NSCLC patients, the combination of Durvalumab, Trametinib and chemotherapy showed promising results in the POSEIDON trial (NCT03164616) [10].

Immunotherapy has already changed the therapeutic algorithm of triple negative breast cancer patients. Rita Nanda (Chicago, USA) showed the results of the Impassion130 trial that led to the accelerated FDA approval in 2019 of Nab-paclitaxel plus Atezolizumab in PD-L1 positive triple negative breast cancer (TNBC) metastatic patients [11]. The Keynote-355 trial evaluated Pembrolizumab in association with chemotherapy and demonstrated a treatment benefit limited to PD-L1⁺ tumors (CPS > 10 using DAKO 22C3), which granted FDA accelerated approval on November 13^th, 2020 [12]. In Stage II-III TNBC, as neoadjuvant treatment associated to chemotherapy, both Pembrolizumab (Keynote522) and Atezolizumab (IMpassion 131) were associated with improvement in pathologic complete response (NCT0303648; NCT03125902). Finally, Rita Nanda presented encouraging data form the I-SPY 2, a phase II platform trial, that used clinical biomarkers to classify breast cancer into 10 subtypes and assign the treatment arm, with the goals to tailor the treatment fitting the patient best (NCT01042379).

Session 2. Adaptive and trained immunity in health and cancer

The Società Italiana di Immunologia, Immunologia Clinica ed Allergologia (SIICA) contributed to the organization of Session 2. The concept of epigenetic imprinting and editing of the immune response was discussed in this session by exploring its relevance in cancer progression and in the implementation of immunotherapeutic approaches. Angela Santoni (Rome, Italy), Catherine Sautes-Fridman (Paris, France), Marco Cassatella (Verona, Italy) and Renato Ostuni (Milano, Italy) acted as discussants in this session.

Mihai Netea (Bonn, Germany) discussed the metabolic status in trained monocytes, by showing that the metabolite mevalonate, of the cholesterol biosynthetic pathway, mediated training via activation of insulin growth factor 1 receptor and mTOR and subsequent histone modifications, in inflammatory pathways [13]. Statins, which block mevalonate generation, by interfering with the biosynthetic enzyme HMG-CoA, prevent trained immunity induction. Monocytes of patients with hyper immunoglobulin D syndrome, who are mevalonate kinase deficient and accumulate mevalonate, display constitutive trained immunity, along with typical attacks of sterile inflammation. He also showed that functional reprogramming of hematopoietic stem and progenitor cells (HSPCs) and peripheral monocytes characterize the induction of trained immunity and the beneficial effects of Bacille-Calmette-Guérin (BCG) vaccination, with a major difference in HPSC transcriptome and a bias toward myelopoiesis [14]. A double-blind randomized trial, showed that BCG vaccination is safe and can protect the elderly against new infections. On this line, Mihai showed how intravenous administration of BCG protects mice against lethal SARS-CoV-2 challenge and how trained immunity may represent a tool against a pandemic [15].

Triantafyllos Chavakis (Dresden. Germany) discussed the relevance of trained granulopoiesis in cancer. He showed that certain infections (e.g., Candida albicans—ß-glucan), vaccines (e.g., BCG) or Western diet can promote an enhanced response of myeloid cells to a secondary challenge, and ß-glucan-induced long-term myelopoiesis/granulopoiesis bias is transmissible to recipient mice [16]. He questioned as to whether trained immunity is involved in the anti-tumor response of beta-glucan. Indeed, ß-glucan enhances antitumor immune responses by regulating differentiation and function of monocytic myeloid-derived suppressor cells. ß-glucan treatment subverted the suppression of myeloid-derived suppressor cells by inducing PMN-MDSC apoptosis and M-MDSC differentiation to antigen presenting cell (APC) in cancer. In the B16-F10 melanoma model, innate immune training via ß-glucan inhibited tumor growth [17]. The anti-tumor effect of ß-glucan-induced trained immunity was associated with transcriptomic and epigenetic rewiring of granulopoiesis and neutrophil reprogramming toward an anti-tumor phenotype, a process that required type-I interferon (IFN) signaling. Noteworthy, trained neutrophils suppressed tumor growth in a ROS-dependent manner, whereas inhibition of type-I IFN signaling abrogated the innate immune training of neutrophils toward an anti-tumor phenotype. He concluded that appropriate rewiring of granulopoiesis is a novel therapeutically relevant anti-tumor facet of trained immunity.

Miriam Merad (New York, USA). After reviewing the successes of immunotherapy, Miriam Merad discussed the interactions between APCs and T cells as central events for an effective antitumor response. Her group performed single-cell mapping analysis of NSCLC, hepatocellular carcinoma (HCC), colorectal cancer (CRC) lesions during treatment with checkpoint blockade, using a CITE-Seq approach. The analysis revealed common myeloid patterns across patients and across tumor types. They identified a lung cancer activation module (LCAMhi), consisting of PDCD1⁺ CXCL13 + activated T cells, IgG⁺ plasma cells, and SPP1⁺ macrophages, which was enriched in multiple NSCLC cohorts [18]. Further, using single-cell RNA sequencing in human and mouse non-small-cell lung cancers, they identified a cluster of DCs named ‘mature DCs enriched in immunoregulatory molecules (mregDCs), co-expressing immunoregulatory genes (Cd274, Pdcd1lg2 and Cd200) and maturation genes (Cd40, Ccr7and Il12b) [19]. These mregDCs have been found in normal tissues and in other inflammatory conditions (i.e., mouse normal lung and lymph nodes, human lung donors, human lung fibrosis). Upon tumor antigen uptake, DC1 and DC2 may undergo a molecular transformation (mregDC) expressing both regulatory and immunogenic programs and a migratory program to guide them to tertiary lymphoid structures (TLS) or lymph nodes (LN). These events are paralleled by PD-L1 expression, through engagement of the receptor tyrosine kinase AXL, while upregulation of interleukin (IL)-12 depends strictly on IFNγ and is controlled negatively by IL-4 signaling.

Claudio Tripodo (Palermo, Italy) discussed how recombination and revision of the TCR machinery in the tumor microenvironment hints at the rising immune pressure, suggesting that the interface between T cells and tumor cells has prognostic significance. This assumption was based on the observation that the clonal status of TILs and TME is variably associated with prognosis in the presence or absence of immune checkpoint blockade [20]. He hypothesized that within the TME, TILs could re-express key elements of the TCR recombination machinery via gene recombination depending on RAG1/2. Signs of RAG1/2 expression events were indeed detected in the TME and increased expression of rag1/2 and dntt was observed along with T cell infiltration, in a model of DNA mismatch repair protein Mlh1-deficient 4T1 tumor [21]. In agreement, analysis of harmonized single-cell RNA sequencing data sets of human cancers identified a very small fraction of tumor-associated T cells, characterized by the expression of recombination/revision machinery transcripts.

At the end of Session 2, Pier Francesco Ferrucci (Milan, Italy) introduced the Giorgio Parmiani Keynote Lecture 2021. He briefly honored the memory of Giorgio Parmiani, enthusiastic founder of the NIBIT and its first president, who passed away on March 21, 2021. Born in 1938, Giorgio Parmiani was a charismatic and internationally recognized pioneer in multiple fields of cancer immunobiology. In 2008, he was awarded the Smalley Price from the Society for Immunotherapy of Cancer (SITC), and in 2020, he and his teams received the SITC Team Science Award, being the face of NIBIT in the World Immunotherapy Council since 2010. The Giorgio Parmiani Keynote Lecture 2021 was honored to Bernard A. Fox (Providence, USA), who, among the many career achievements, also served as SITC president. Berny Fox delivered a lecture on: Translation, An Iterative and Team Process – Our Path to the Development of Triplet Cancer Immunotherapy. Starting from the evidence that we still do not know why not all metastatic cancer patients benefit from immunotherapy, he proposed to abandon the T cell-centric view, and focus instead on the contribution of NK cells, B cells and innate effectors. B cells can show effector mechanisms through complement activation, antibody production, direct cytotoxicity, induced phagocytosis and apoptosis. On the other hand, they could also act as suppressors of the immune responses. Cancer patients have broad anticancer immunity against non-mutated epitopes and shared antigens, showing a diversity of antigen-specific responses. In this sense, IgG antibodies could identify targets of CD8 T cell response, and once stimulated with shared antigens and cytokines, can “re-activate” T cells to kill cancer cells. Coordinated responses to individual tumor antigens by IgG antibody and CD8⁺ T cells, both recognizing component of the same long peptide and the tumor, have been demonstrated following cancer vaccination. On the other hand, it is good news that the immune system recognizes not-mutated shared antigens in different cancers, said Fox, so the challenge is to identify a vaccine with large number of overexpressed cancer antigens to prime or “re-activate” T cells. Hence, we can start the engine, accelerate, and relieve the brake simultaneously by combining vaccination with stimulating antibodies and immune check point blockade. Triple combination immunotherapy clinical trials are ongoing using complex vaccines, plus co-stimulation with anti-OX40 or anti-GITR, plus anti-PD1.

Session 3. Metabolism at the intersection between cancer and immunity

The Società Italiana di Cancerologia (SIC) helped the NIBIT to organize Session 3, which was centered on the metabolic switch in TME. Paola Chiarugi (Firenze, Italy), Antonio Rosato (Padova, Italy), Vincenzo Russo (Milan, Italy) and Ivan Zanoni (Boston, USA) were invited to chair and discuss this issue.

In recent years, metabolism has been reported to influence both tumor and immune cells. Several reports have recently shown that the pharmacologic and genetic manipulation of metabolic pathways restores antitumor immune responses by activating or suppressing distinct cellular elements in the TME. Marina Garassino (Chicago, USA) discussed how obesity may interfere with spontaneous or induced immune responses [22].

Antonio Sica (Novara, Italy) discussed the pro-tumor role of myeloid cells and how to target them to unleash antitumor immune responses. Particularly, he discussed the steps of the emergency myelopoiesis, which determines the appearance of RORC1/RORγ⁺ myeloid cells infiltrating advanced tumors [23]. He also described strategies to target pro-tumor myeloid cells by antibodies recognizing colony stimulating factors or their receptors, such as anti-colony stimulating factor 1 receptor, or by drugs antagonizing the CXCR4 chemokine receptor, which is involved in the mobilization of myeloid precursors. He introduced the role of the nicotinamide phosphoribosyltransferase (NAMPT) enzyme in myeloid cell mobilization. NAMPT is the rate-limiting enzyme in the nicotinamide adenine dinucleotide pathway that converts nicotinamide to nicotinamide mononucleotide, thus controlling pro-tumor myeloid cell mobilization [24]. Finally, he focused on a newly identified pro-tumor subset of F4/80^hiCD115^hiC3aR^hi TAMs expressing the heme-oxygenase 1 enzyme and involved in iron metabolism. This subset favors immunosuppression, angiogenesis and epithelial-to-mesenchymal transition. F4/80^hiCD115^hiC3aR^hi TAMs originate from specific F4/80⁺HO-1⁺ bone marrow precursors and accumulate in the blood of patients affected by cancer. Of note, genetic or pharmacologic targeting of this subset blocked metastasis formation and improved anticancer immunotherapy. The relative expression of HO-1 in peripheral monocyte subsets, as well as in tumor lesions, impacted on the survival of advanced melanoma patients [25].

Roberta Zappasodi (New York, USA) described the role of glucose metabolism in Treg activity and how uncoupling glycolytic metabolism in Treg improves cancer immunotherapy. She showed that knock down of the gene encoding lactate dehydrogenase A in glycolytic tumors (glycolysis-defective tumors) improves tumor responses to CTLA-4 blockade. Investigating TIL subsets sensitive to this mechanism, she observed that CTLA-4 blockade-induced Treg instability in glycolysis-defective tumors, which was dependent on local lactate:glucose ratio. Finally, she observed that CTLA-4 blockade triggered CD28 signaling in Tregs ultimately promoting Treg glycolysis. Glycolysis supported Treg proliferation at the cost of reduced functional stability, namely increased IFN-γ production associated with reduced Treg suppression [26].

Dmitry Gabrilovich (Gaithersburg, USA) discussed the role of lipids and lipid metabolism in the regulation of MDSCs. He showed that PMN-MDSCs blocked cross-presentation by DCs. This effect was associated with the transfer of oxidized lipids to DCs. Moreover, he showed that PMN-MDSC generate oxidized lipids through the activity of myeloperoxidase (MPO). Indeed, MPO-deficient PMN-MDSCs did not dampen DCs. Of note, the pharmacological inhibition of MPO potentiated the antitumor effects of immune checkpoint blockade in different tumor models [27]. In addition, he discussed the role of endoplasmic reticulum (ER) stress response in the suppressive activity of tumor-infiltrating MDSCs. He showed that the acquisition of immune-suppressive activity by PMN-MDSCs in cancer was also controlled by IRE1α and ATF6 pathways of the ER stress response. Blockade of the ER stress response restored antitumor immune responses through the abrogation of PMN-MDSC activity [28]. Finally, he investigated the reactivation of dormant tumor cells, which is responsible for cancer patients’ mortality. He showed that stress hormones induced a rapid release of proinflammatory S100A8/A9 proteins by neutrophils. S100A8/A9 induced the activation of MPO, leading to the accumulation of oxidized lipids in these cells. Once released, these lipids upregulated the fibroblast growth factor pathway in tumor cells, favoring the formation of new tumor lesions. Finally, targeting of S100A8/A9 proteins abrogated stress-induced reactivation of dormant tumor cells [29].

Finally, Teresa Manzo (Milan, Italy), selected abstract, reported the identification of lipids endowed with the potential to differentiate antigen-specific T cells toward T cell memory cells. This metabolic rewiring of human and mouse T cells can be exploited to generate more potent tumor-specific CD8⁺ T cells for adoptive cell therapy purposes [30].

Session 4. Targeting immune-related tumor cell-extrinsic mechanisms

Section 4 focused on tumor cell-extrinsic mechanisms that modulate cancer immunity also impacting cancer immunotherapy. The session was jointly organized with the Alleanza Contro il Cancro (ACC) and witnessed Paola Nisticò (Rome), Matteo Bellone (Milan), Vincenzo Bronte (Verona) and Rugero De Maria (Rome) as discussants.

The tumor microenvironment organizes a metabolic barrier, hampering antitumor functions and promoting in turn resistance to immunotherapy [31]. Massimiliano Mazzone (Leuven, Belgium) presented interesting data emerging from computational analysis of the genes upregulated in human and murine transcriptomic and metabolomic datasets from non-responder vs responder to ICIs. Mazzone and collaborators identified an enzyme among the upregulated genes correlating to ICI resistance. The expression of this pyrimidine salvage pathway enzyme was acquired by pancreatic ductal adenocarcinoma (PDAC) tumor epithelial cells and correlated with poor disease outcome. In PDAC mouse models, enzyme knock down in cancer cells promoted tumor regression when combined with ICI, which correlated with increased number of activated CD8⁺ T cells and reduced numbers of immunosuppressive TAMs in tumors. The mechanism is still under investigation. Thus, metabolic cues might be exploited for therapeutic purposes to overcome resistance to cancer immunotherapy [32].

To date, PDAC remains a highly aggressive and treatment-refractory disease, characterized by stroma-rich and desmoplastic areas characterized by the presence of carcinoma-associated fibroblasts (CAFs) and stellate cells. In this regard, modification of the tumor stroma, with a particular focus on CAFs, is an attractive strategy to improve PDAC patients’ outcome. Shannon Turley (San Francisco, USA) reported on a recent work from her group aimed at defining the nature of the stromal compartment and its heterogeneity during PDAC evolution [33]. They performed bulk and single-cell RNAseq of stromal cells in normal tissues, nonmalignant adjacent tissue, and early and advanced tumors from Pdx1cre/ + ;LSL-KrasG12D/ + ;p16/p19flox/flox (KPP) mice. The analysis revealed fibroblast heterogeneity in healthy pancreas, which dictate the development trajectory of CAFs in the KPP mouse model. Among the different CAF clusters, two major subtypes arose after mapping the transcriptional changes during PDAC evolution. One was of particular interest due to its high representation in late stages of tumorigenesis and its TGFβ activation signature, which correlated with poor prognosis in PDAC patients. The transmembrane protein LRRC15 (Leucine-Rich Repeat Containing 15) was sufficient to distinguish TGFβ-driven CAFs from other fibroblast subsets in PDAC specimens. LRRC15 protein can be upregulated by TGFβ and is absent/low in normal tissues but strongly expressed in the stromal compartment of several tumor types [i.e., pancreatic, breast, and head and neck cancers; ref. [34]]. The presence of LRRC15⁺ CAFs was validated in published data of patients with PDAC [35], where the TGFβ-driven cluster represent about 52% of CAFs. Additionally, high expression of LRRC15 CAF signature and worse outcome were found in urothelial bladder cancer patients treated with anti-PD-L1 (atezolizumab), specifically in immune-excluded tumors. Importantly, also PDACs exhibited similar immune-desert landscapes. Additional data about the function of LRRC15⁺ CAFs and their reprogramming are needed to optimize fibroblast modulation and immunotherapy.

The talk of Kathy McCoy (Calgary, Canada) was the trait d'union between metabolism and microbiota. She elegantly described how our microbes may influence the treatment of cancer through metabolites. She started from the observation that anti-PD-L1 and anti-CTLA4 allowed better tumor control and accumulation of tumor-infiltrating lymphocytes (TILs) in a CRC model driven by dextran sulfate sodium and azoxymethane [36]. This benefic effect could be transferred by transplanting microbial species (e.g., Bifidobacterium pseudolongum) or serum from responders. In the serum, inosine produced by Bifidobacterium pseudolongum and Akkermansia mediated tumor control by activating the cognate adenosine A2A receptor on T cells in the presence of costimulatory signals. However, better tumor control was obtained by combining these approaches with anti-CTLA4, which decreased gut barrier function and favored systemic translocation of inosine and activation of antitumor T cells [36].

The selected abstract of this session was from Laura Lucia Cogrossi (Milan, Italy). She reported on a recent publication showing that distinct Prevotella species differently impact induction of Th17 cells and in vivo tumor growth [37]. She investigated the mechanisms by which Prevotella heparinolytica (Ph) and Prevotella melaninogenica (Pm) interact with dendritic cells, inducing the release pro-inflammatory cytokines. Ph favored the release of cytokines promoting the switch to Th17 cells. Preliminary data suggested that the interaction between DCs and the two Prevotella strains occurs through different toll-like receptors.

Together the last two presentations taught us that mere taxonomy of commensal bacteria is not enough to understand the relevant interactions with the immune system of the host.

Conclusions

The XIX NIBIT meeting smoothly rolled out in a stimulating atmosphere, regardless of the hurdles imposed by COVID-19 pandemic. Delegates were updated on the most recent discoveries in cancer immunology and immunotherapy. Additionally, several findings collected in inflammatory diseases including COVID-19 and reported at the meeting, provided relevant clues to better understand cancer-immune cell interactions. Supplementary Table 1 summarizes topics and take home message of every presentations. Sessions were rich in discussions and the youngest investigators had the opportunity to confront established researchers. The XIX annual meeting of the NIBIT was adjourned with the promise to meet in person in Padova in 2022.

Supplementary Information

Below is the link to the electronic supplementary material.

Abbreviations

ACC

Alleanza contro il cancro

ACT

Adoptive cell therapy

AIOM

Associazione Italiana di oncologia medica

AML

Acute myeloid leukemia

APC

Antigen presenting cell

BCG

Bacille-Calmette-Guérin

CAF

Carcinoma-associated fibroblast

CDA

Cytidine deaminase

CRC

Colorectal cancer

DC

Dendritic cell

DFS

Disease free survival

HCC

Hepatocellular carcinoma

HSPC

Hematopoietic stem and progenitor cell

ICI

Immune checkpoint inhibitor

IFN

Interferon

IL

Interleukin

LN

Lymph node

LRRC15

Leucine-rich repeat containing 15

MDSC

Myeloid-derived suppressor cell

M-MDSC

Monocyte myeloid-derived suppressor cell

MM

Multiple myeloma

MPO

Myeloperoxidase

mregDC

Dendritic cell enriched in immunoregulatory molecules

NAMPT

Nicotinamide phosphoribosyltransferase

NIBIT

Italian network for tumor biotherapy

NSCLC

Non-small cell lung cancer

PMN-MDSC

Polymorphonuclear myeloid-derived suppressor cell

PDAC

Pancreatic ductal adenocarcinoma

SIC

Società Italiana di cancerologia

SIICA

Società Italiana di Immunologia, Immunologia Clinica ed Allergologia

SITC

Society for immunotherapy of cancer

TAM

Tumor-associated macrophage

TIL

Tumor-infiltrating lymphocyte

TLS

Tertiary lymphoid structure

TNBC

Triple negative breast cancer

UDP

Uridine diphosphate

UTP

Uridine triphosphate

Author contributions

All authors contributed to writing the manuscript. MB collected and assembled contributions from all authors. All authors revised and approved the final version of the manuscript.

Funding

This meeting was supported in part by unrestricted grants from AstraZeneca, Becton Dickinson (BD), Bristol-Meyers Squibb, Diatech Labline, Fluidigm, Incyte, Merck Sharp & Dome (MSD), Milteny Biotec, Nano String, Novartis, Pierre Fabre Oncology, Promega, and under the auspices of the AIOM, the Associazione Italiana Oncologia Toracica (AIOT), the Fondazione Associazione Italiana per la Ricerca sul Cancro (AIRC), the ACC, the Fondazione Melanoma onlus, the Fondazione Grazia Focacci, the Istituto Oncologico Veneto (IOV), the Fondazione Pezcoller, the SIC, the SIICA, and the Women for Oncology Italy.

Declarations

Conflict of interest

PFF has received honorarium for advisory board participation from: Bristol Meyers Squibb, Novartis, MSD, Pierre Fabre and Roche. VB reports relationship with IoBiotech Aps and Codiak BioScience (personal fees), outside the submitted work. All other authors have no conflict of interest to declare.