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. 2021 Apr 29;29(6):1958–1969. doi: 10.1016/j.ymthe.2021.04.029

The roles of PD-1/PD-L1 in the prognosis and immunotherapy of prostate cancer

Yichi Xu 1, Gendi Song 1, Shangdan Xie 1, Wenxiao Jiang 1, Xin Chen 1, Man Chu 1, Xiaoli Hu 2,∗∗, Zhi-wei Wang 1,3,∗
PMCID: PMC8178461  PMID: 33932597

Abstract

Multiple studies have confirmed that programmed cell death 1/programmed cell death ligand-1 (PD-1/PD-L1) and immune checkpoint inhibitors (ICIs) targeting PD-1/PD-L1 play pivotal roles in the treatment of numerous tumors. Patients suffering from cancer are provided hope in the form of immunotherapy. In this review, we discuss the finding that high PD-L1 expression is associated with poor clinical outcomes in prostate cancer patients. Some molecules exert their antitumor effects by downregulating PD-L1 expression in prostate cancer. Additionally, we discuss and summarize the important roles played by anti-PD-1/PD-L1 immunotherapy and its combination with other drugs, including chemotherapy and vaccines, in the treatment of prostate cancer.

Keywords: PD-1, PD-L1, immunotherapy, prostate cancer, vaccines

Graphical abstract

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We describe that high PD-L1 expression is associated with poor outcomes in prostate cancer patients. Moreover, we summarize the roles played by anti-PD-1/PD-L1 immunotherapy in the treatment of prostate cancer. This review suggests that anti-PD-1/PD-L1 immunotherapy in combination with other treatments might improve the efficacy of immunotherapy.

Introduction

In recent years, immunotherapy against cancer has yielded encouraging results and significantly changed the treatment landscape owing to its efficacy and minimal side effects.1 Programmed cell death 1 (PD-1), also known as cluster of differentiation 279 (CD279), is encoded by the PDCD1 gene located on chromosome 2q37.2 PD-1 is widely expressed in a range of immune cells, such as T cells and dendritic cells.3 The B7 family member programmed cell death ligand-1 (PD-L1, B7-H1, or CD274) was the first discovered ligand of PD-1. The gene encoding PD-L1 is located on human chromosome 9 p24.1, and it is widely expressed in numerous tumor cells.4, 5, 6 Under physiological conditions, the PD-1/PD-L1 pathway protects tissues from autoimmune attack and maintains peripheral tolerance.7 Nonetheless, PD-1 binds to its ligand PD-L1 on tumor cells, which leads to tumor immunosuppression and the immune tolerance of cancer cells, thereby promoting immune escape.8 Tumor immune escape is a common phenomenon in which tumor cells can grow and metastasize by avoiding the recognition and attack of the immune system.9,10 This is an important strategy for tumor survival and development. Accordingly, in recent years, immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 axis have become one of the major directions for cancer immunotherapy to reverse immunosuppression and to restore activity of the immune system against tumors.11,12

Prostate cancer is the second most common malignant tumor among men worldwide, and it is also the fifth leading cause of cancer-related deaths.13 It is estimated that in 2020 there were more than 1.4 million new prostate cancer cases and 375,000 deaths due to this disease worldwide.13 In 2021, it is estimated that there will be 248,530 new cancer cases and 34,130 deaths from prostate cancer in the United States.14 For patients with metastatic prostate cancer, various treatment options for metastatic castration-resistant prostate cancer (mCRPC) with hormones, chemotherapy, and radiopharmaceuticals have shown significantly increased overall survival (OS), but ultimately metastatic prostate cancer is still incurable.15, 16, 17 Fortunately, PD-1/PD-L1 immune checkpoint inhibitors have been approved by the U.S. Food and Drug Administration (FDA) due to their unprecedented advantages in treating different cancer types, including melanoma,18 urothelial cancer,19 and renal cell carcinoma.20 Anti-PD1 antibody nivolumab immunotherapy has a higher overall response in comparison with melanoma patients treated with chemotherapy.21 In addition, nivolumab is also used to treat patients with advanced renal carcinoma due to its efficacy and safety.22 The anti-PD-L1 antibody atezolizumab was approved for use in urothelial carcinoma patients who failed chemotherapy or were platinum ineligible.23 Consequently, the response rate was increased in the atezolizumab immunotherapy group, and the response rate was associated with PD-L1 expression in urothelial carcinoma patients.23

In prostate cancer, targeting the immune system might represent a promising approach for treatments in the future. Nevertheless, tumors that respond to ICIs show higher levels of immune infiltration or interferon (IFN) markers, which indicates an inflammatory phenotype of T cells.24 Melanoma and lung cancer show a high response rate to ICIs and are often called “hot tumors.” In contrast, prostate and pancreatic tumors have low immune infiltration levels and are commonly referred to as “cold tumors.”24 Fortunately, the combination of PD-1/PD-L1 blockade drugs and other therapeutic methods have shown promising effects in prostate cancer. Our review article describes the mechanism of tumor immune escape by blocking the PD-1/PD-L1 pathway in prostate cancer. We further discuss PD-1/PD-L1 blockade therapy in combination with various other drugs as innovative treatment strategies to improve therapy efficacy. Therefore, blockade of PD-1 and PD-L1 might be a promising strategy for prostate cancer therapy.25

Expression of PD-1/PD-L1 and its clinical significance in prostate cancer

High expression of PD-1/PD-L1 is associated with the clinical features of prostate cancer.26 Compared with normal prostate epithelium, the PD-1 promoter is significantly hypermethylated in cancer tissues, and PD-1 methylation is negatively related to the expression of PD-1 mRNA in prostate cancer.27 The PD-1 methylation level is positively associated with a higher preoperative prostate-specific antigen (PSA) score, Gleason grade, and advanced pathological tumor category and is an unfavorable prognostic factor for biochemical recurrence (BCR)-free survival. Moreover, PD-1 methylation has a positive association with androgen receptor (AR) activity and the presence of ERG gene fusion. Androgen receptor and ERG might influence PD-1 promoter methylation, and androgen receptor could affect the subcellular interaction between PD-1 and PD-L1, resulting in regulating autoimmune responses via PD-1.27 Therefore, analysis of PD-1 promoter methylation can contribute to identifying patients who may benefit from adjuvant therapy after radical prostatectomy.27 A growing body of literature suggests that PD-L1 expression is upregulated in prostate cancer tissues compared to paired normal tissues.26,28 More than half of the cases tested showed moderate to high levels of PD-L1 expression, which was positively related to proliferation, Gleason score, and androgen receptor expression in patients with aggressive primary prostate cancer.26 Furthermore, PD-L1 positivity was confirmed as an independent unfavorable prognostic indicator for BCR by multivariate Cox analysis.26 Additionally, PD-L1 was highly expressed in high-risk patients with prostate cancer, and it was also an unfavorable prognostic biomarker for predicting high-risk prostate cancer among those treated with adjuvant hormonal therapy after tumor surgery.29 Sharma et al.30 analyzed the relationship between PD-1/PD-L1 expression and clinicopathologic features by tissue microarray from radical prostatectomy patients. They found that the expression of PD-L1 in tumor cells was more common in tumor high-stage or lymph-node-positive cases, but the expression of PD-1 in tumor cells was not associated with tumor stage.30 A meta-analysis revealed similar results to those in another study.31 PD-L1 expression is associated with unfavorable biochemical recurrence-free survival. PD-L1 expression tends to be elevated in high Gleason score cases and androgen-receptor-positive cases, but age, pathological stage, lymph node metastasis, and preoperative PSA levels are not correlated with PD-L1 levels.31 Notably, it was shown that PD-L1 tends to be expressed in aggressive prostate cancer and is associated with a poor clinical prognosis.31

A recently published study found that PD-L1 was frequently expressed in tumor-associated nerves (TANs) and inversely involved in CD8+ tumor-associated lymphocytes (TALs), suggesting that neuroimmunological interactions possibly contribute to the immune-suppressive microenvironment.32 A higher density of PD-L1+ TANs was positively associated with BCR in Kaplan-Meier survival analysis.32 This indicated that combination immune treatment of neural PD-L1 and TALs should be used for clinical applications in prostate cancer in the future.32 Petitprez et al.33 discovered that the risk of distant metastasis of PD-L1-positive tumors is almost four times higher than that of PD-L1-negative tumors. They also found that PD-L1 expression is positively correlated with CD8+ T cell density. The expression of PD-L1 in tumor cells and a high density of CD8+ T cells in tumors are associated with a higher risk of clinical progression in men with lymph-node-positive prostate cancer.33 PD-L1 expression is observed not only in cancer cells but also in circulating epithelial tumor cells (CETCs) of cancer patients.34 For instance, a study showed that PD-L1 was highly expressed on CETCs in 100% of prostate cancer patients.34 One study found that only 7.7% of cases showed positive staining of PD-L1 in primary prostate acinar adenocarcinoma, whereas 42.9% of small cell carcinomas of the prostate and 31.6% of mCRPCs show increased levels of PD-L1.35

PD-L1 DNA methylation (mPD-L1) is higher in prostate tumor tissues than in normal tissues. In addition, higher mPD-L1 levels are correlated with shorter BCR-free intervals in prostate cancer patients, indicating that mPD-L1 is an unfavorable prognostic biomarker for prostate cancer patients.36 A polymorphism of the PD-L1 gene (rs4143815), as a new immune genetic marker for predicting BCR in prostate cancer, provides new insights into the radiotherapy/immune system interaction, which may be useful in developing new anti-PD-L1 therapies to treat prostate cancer.37 Together, these findings indicate that methylation and polymorphism of PD-L1 play critical roles in prostate tumorigenesis.

One investigation found that metastatic melanoma releasing exosomal PD-L1 could indicate an unfavorable response to anti-PD-1 therapy.38 The role of exosomal PD-L1 in prostate cancer for predicting the anti-PD-1 response and treatment outcomes has not been well investigated.

Posttranslational modifications (PTMs) regulate PD-1/PD-L1

PTMs include glycosylation, phosphorylation, and ubiquitination, which play a key role in the regulation of PD-1/PD-L1 protein stability and protein interactions.39 For instance, glycosylation of PD-L1 is essential for enhancing the stability of the PD-1/PD-L1 protein and consequently improving the immune escape ability in cancer cells.40 Additionally, the PD-1/PD-L1 pathway is regulated by ubiquitination or deubiquitination and plays an important role in immunotherapy.41 Cyclin D-CDK4 modulates the stability of PD-L1 by Cullin-3SPOP; thus, CDK4/6 inhibitor in combination with PD-1/PD-L1 blockade can increase the therapeutic efficacy of immunotherapy and suppress tumor progression.42 FBXO38 is an E3 ubiquitin ligase of PD-1 that regulates PD-1 by Lys48-linked polyubiquitination. However, in human tumor tissues and mouse cancer models, the transcription levels of FBXO38 were downregulated in tumor-infiltrating T cells. Interleukin-2 (IL-2) treatment rescued the transcription of FBXO38, thus downregulating PD-1 levels in PD-1-positive T cells. These data reveal another strategy to block PD-1 through regulation of the FBXO38 pathway.43 Li et al.44 found GSK3β phosphorylation motifs (S/TXXXS/T, where S is serine, T is threonine, and X is any amino acid) at T180 and S184 in the extracellular domain of PD-L1. PD-L1 phosphorylation by GSK3β leads to the association of PD-L1 with the E3 ligase β-TrCP, which results in the degradation of PD-L1. Notably, PD-L1 acetylation has also been identified in human cancer.45 A recent study found that PD-L1 was transferred from the plasma membrane to the nucleus by interacting with components of endocytosis and nucleocytoplasmic transport pathways. This mechanism was regulated by p300-mediated acetylation and HDAC2-dependent deacetylation of PD-L1. Genetically or pharmacologically, regulating PD-L1 acetylation blocked its nuclear translocation and reprogrammed immune-response-related gene expression, thereby strengthening the antitumor response to PD-1 blockade. Therefore, these results revealed that the nuclear localization of PD-L1 regulates the expression of immune response genes in an acetylation-dependent manner to regulate PD-1/PD-L1 blockade efficacy.45

Signaling pathways regulate PD-1/PD-L1

Increasing amounts of research have revealed that numerous types of upstream signaling pathways modulate PD-L1 expression.28,46,47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57 For example, one study reported that ligand antagonist antibodies failed to inhibit residual suppression of T cell activation through intracellular signaling, such as tonic signaling by PD-1.58 Receptor inhibition by phosphatase recruitment (RIPR) compelled the cell surface receptors that contain the ITAM, ITIM, or ITSM tyrosine phosphorylation motif to cis-connect to the promiscuous cell surface phosphatase CD45, leading to direct intracellular tyrosine residue dephosphorylation. Hence, the RIPR-PD-1 molecule triggered crosslinking of PD-1 to CD45 and consequently repressed tonic and ligand-activated signaling. RIPR-PD-1 promoted the effect of checkpoint blockade and improved the therapeutic efficacy of anti-PD1 antibodies.58 In the following paragraphs, we summarize how key molecules and multiple pathways as well as noncoding RNAs regulate the expression of PD-L1 in prostate cancer cells (Figure 1; Table 1).

Figure 1.

Figure 1

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Effect of the PD-L1/PD-1 signaling pathway in immunotherapy

IL-17, TNF-α, LRP11, IL-6, leptin, MLL3, lncRNA KCNQ1OT1, and lncRNA AMPC upregulate PD-L1 expression and then exert their suppressive roles in tumor immunity. Chemerin, JAK inhibitor 1, miR-195, and miR-16 downregulate PD-L1 expression and then exert their inhibitory effect on tumorigenesis and improve tumor immunotherapy.

Table 1.

Effects of the PD-L1/PD-1 signaling pathway on immunotherapy

Upstream Expression Targets Functions Reference
IL-17 and TNF-α upregulate activate NF-κB and ERK1/2 pathways induces immunosuppressive and tumor immune escape Wang et al.47
LRP11 upregulate activates β-catenin signaling pathway induces immunosuppression Gan et al.28
IL-6 and leptin upregulate activate JAK/Stat3 signaling induces cancer progression Xu et al.46
MLL3 upregulate promotes the binding of to H3K4me1 and Pol II Ser-5p induces tumor growth Xiong et al.50
lncRNA KCNQ1OT1 upregulate sponges miR-15a to suppress CD8+ T cells promotes immune evasion Chen et al.51
lncAMPC upregulate LIF/JAK-1/Stat3 pathway promotes immunosuppression Zhang et al.52
Chemerin/CMKLR1 downregulate activates CMKLR1, PTEN, PD-L1 signaling cascade elevates the effects of immunotherapy Rennier et al.54
JQ1 downregulate reduces PD-L1 expression inhibits tumor development Mao et al.55
JAK inhibitor 1 downregulate inactivates JAK/PD-L1 signaling pathway inhibits the EMT, metastasis, and cancer progression Zhang et al.56
miR-195 and miR-16 downregulate T cell activation activates in the tumor microenvironment and enhances radiotherapy Tao et al.57
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IL-6 and JAK pathway upregulate PD-L1 expression

The JAK-STAT signaling pathway plays essential roles in tumor growth, cell proliferation, and metastasis.59 In prostate cancer, JAK-STAT blockade suppressed the clonogenic recovery of cancer stem-like cells and tumor initiation.60 A study showed that IL-6 activated the JAK-Stat3 signaling pathway, resulting in upregulation of PD-L1 and downregulation of the natural killer (NK) group 2D (NKG2D) ligand in CRPC cells.48 The decrease in PD-L1 and the increase in NKG2D ligand levels caused IL-6-knockdown cells to be more susceptible to NK-cell-mediated cytotoxicity.48 Using PD-L1 antibody and JAK inhibitor (or Stat3 inhibitor) together can produce the most effective cytotoxicity. Another study proposed that the combined inhibition of the JAK1, 2/PD-L1, and Stat3/PD-L1 signaling pathways can increase the activity of immune cytolytic in NK cells against hypoxia-induced CRPC cells, which may provide new targets for CRPC immunotherapy.49 It has also been shown that adipocytes enhance the resistance of NK-cell-induced cytotoxic effects via modulation of PD-L1/NKG2D ligand levels in CRPC cells. Two adipokine molecules, IL-6 and leptin, are important in activating JAK/Stat3 signaling in CRPC cells to regulate changes in PD-L1/NKG2D ligand levels. Adding JAK/Stat3 signal inhibitors or antibodies that neutralize IL-6 or leptin will increase the sensitivity of CRPC cells to NK cells.46 Similarly, one group found that after adding JAK inhibitor 1, the expression of PD-L1 was decreased in CRPC cells.56 It was found that the cell migration ability was reduced, and the expression of epithelial-to-mesenchymal transition (EMT)-related markers was effectively reversed in CRPC cells treated with PD-L1 antibody and JAK inhibitor 1. The results of this study indicate that inhibiting the JAK1/PD-L1 signaling pathway can be a new targeted therapy for CRPC patients via suppression of EMT and metastasis.56

MLL3 promotes PD-L1 expression

Histone methyltransferase mixed-lineage leukemia protein 3 (MLL3) acts as a positive regulator of PD-L1 in prostate cancer cells. It was found that the high expression of PD-L1 and MLL3 in metastatic cancer tissues compared with primary cancer tissues may be due to the binding of MLL3 to the enhancer of PD-L1, leading to the promotion of transcription of PD-L1.50 Silencing of MLL3 reduced the binding activity of H3K4me1 and Pol II Ser-5p in the enhancer and promoter of PD-L1, respectively.50 MLL3 depletion can impair the growth of mouse xenografts and reduce the response of mice to PD-L1 antibody treatment. These findings expand our understanding of PD-L1 transcriptional biological regulation and highlight hidden therapeutic targets to conquer tumor immune escape.50 The expression of the above molecules will promote the immune escape of cancer by promoting the expression of PD-L1. Therefore, the development and progression of prostate cancer can be suppressed by inhibiting the expression of these molecules.

Chemerin suppresses PD-L1 expression

Chemerin, an endogenous leukocyte chemoattractant, recruits innate immune cells through its receptor, chemokine-like receptor-1 (CMKLR1).53 Chemerin upregulates phosphatase and tensin homolog (PTEN) expression and suppresses PD-L1 expression concomitantly.54 CMKLR1 knockdown reduced chemerin-induced PTEN and PD-L1 modulation, exposing a novel CMKLR1/PTEN/PD-L1 signaling cascade. Chemerin treatment obviously reduced tumor metastasis of human prostate cancer cells and tumor growth in vivo.54 Chemerin increased T cell-mediated cytotoxicity by signaling cascades linking chemerin/CMKLR1, PTEN, and PD-L1, which indicated a new therapeutic strategy in which chemerin treatment upregulates PTEN expression and inhibits PD-L1 expression and then enhances the effects of immunotherapy.54

JQ1 inhibits PD-L1 expression

The bromo and extraterminal domain (BET) proteins, which comprise BRD2, BRD3, BRD4, and BRDT, are essential during the progression of cancer.61 Inhibition of the BET bromine domain can increase the expression of major histocompatibility complex (MHC) I and the immunogenicity of prostate cancer cells. It has been revealed that targeting the BET bromodomain with the small-molecule inhibitor JQ1 can reduce PD-L1 expression and inhibit tumor development in patients with prostate cancer.55

IL-17, TNF-α, and LRP11 upregulate PD-L1 expression

A study demonstrated that IL-17 and tumor necrosis factor-α (TNF-α) individually upregulated PD-L1 expression in prostate cancer cells by triggering the activity of the nuclear factor κB (NF-κB) and ERK1/2 signaling pathways, which may lead to the induction of an immunosuppressive tumor microenvironment and tumor immune escape by increasing the expression level of PD-L1.47 An investigation reported that low-density lipoprotein (LDL) receptor-related protein 11 (LRP11) promoted PD-L1 expression by activating the β-catenin signaling pathway in prostate cancer, which could contribute to immunosuppression.28 Moreover, LRP11 and PD-L1 levels were increased in prostate cancer compared to paired normal tissues. Moreover, a positive correlation was found between the expression of LRP11 and PD-L1 in prostate cancer patients.28

miRNAs regulate PD-L1 expression

MicroRNAs (miRNAs) are endogenous noncoding small RNAs that participate in necessary biological processes such as cell proliferation and differentiation.62 Recently, several studies have revealed that miRNAs regulate the expression of PD-L1 in human cancers.63,64 Some miRNAs exert antitumor immunity effects by suppressing the PD-1/PD-L1 axis and targeting multiple molecular pathways, such as STAT, ZEB, and PI3K/Akt.64 For instance, one group reported that miR-195 and miR-16 inhibited PD-L1 expression in prostate cancer cells.57 In addition, by blocking PD-L1 expression, the expression of miR-195 and miR-16 is restored by T cell activation in the tumor microenvironment, thereby enhancing radiotherapy.57 High levels of miR-195 and miR-16 are positively correlated with the biochemical recurrence-free survival rate of prostate cancer patients.57 Strikingly, the expression levels of miR-195 and miR-16 are negatively correlated with PD-L1 and PD-1 expression.57

lncRNAs regulate the PD-L1 expression

Long noncoding RNAs (lncRNAs) play important roles in the modulation of PD-L1 expression in prostate cancer. lncRNA KCNQ1OT1 sponges miR-15a to suppress CD8+ T cell cytotoxicity and promote the progression of prostate cancer through upregulation of PD-L1 expression.51 Mechanistically, miR-15a binds to the 3′ UTR of PD-L1 directly and then inhibits PD-L1 expression, causing antitumor effects in prostate cancer cells. Hence, the lncRNA KCNQ1OT1/miR-15a/PD-L1 axis maintains malignant phenotypes and immune evasion, indicating that upregulation of miR-15a or downregulation of lncRNA KCNQ1OT1 and PD-L1 may be a novel therapy approach for prostate cancer patients.51 Additionally, lncRNA activated in metastatic prostate cancer (lncAMPC) increases the expression of leukemia inhibitory factor (LIF) to maintain the stability of PD-L1 expression through the JAK-1/Stat3 pathway. lncAMPC-activated LIF partially led to PD-L1-mediated immunosuppression, which may be a therapeutic target.52

Defective mismatch repair (dMMR) status is correlated with PD-L1 expression

Mismatch repair (MMR) gene mutations are rare in patients with prostate cancer. However, advanced prostate cancer with MMR mutations seems to be particularly sensitive to hormone therapy and anecdotal reactions to PD-1 inhibitors (such as pembrolizumab).65 The MMR system is a high-fidelity single-stranded repair mechanism after replication that can identify and reverse insertion/deletion (indel) loops and DNA base mismatches.66 The dMMR can lead to microsatellite instability and a hypermutation phenotype, which is related to chemotherapy resistance but sensitive to immunotherapy.67 In advanced prostate cancer with dMMR mutational signatures, a large number of immune transcripts are overexpressed, such as the immune-checkpoint-related transcript PD-L1, and the possibility of PD-L1 positivity in dMMR mCRPC is higher, thus providing further evidence of dMMR as a potential predictive biomarker for immune checkpoint suppression in fatal prostate cancer.68 Moreover, there was a correlation between the loss of ≥2 MMR proteins and a higher PD-L1 expression level in prostate cancer cells, and the risk of biochemical recurrence is higher in immune cells with ≥1 MMR protein expression loss and PD-L1 tumor infiltration. Hence, it is helpful to perform immunohistochemical detection of MMR proteins together with PD-L1 to predict tumor recurrence.69

Anti-PD1/PD-L1 therapy in combination with other treatments

A combination of immunotherapy with various treatments might achieve synergistic effects in human cancers. Transforming growth factor β (TGF-β), a multifunctional cytokine, is related to a poor prognosis and plays a key role in various kinds of cancers by triggering immune escape, metastasis, angiogenesis, and EMT.70,71 A recent study revealed that TGF-β restricted T cell infiltration and inhibited the tumor response to PD-L1 blockade.72 ADAR1 is a related factor that regulates the innate immune response and has been found to exert multiple functions in biological or pathological conditions.73 Loss of ADAR1 in tumors increased their sensitivity to PD-1 checkpoint blockade due to inactivation of antigen presentation.74 Group 2 innate lymphoid cells (ILC2s) can be detected in cancers, and they regulate cancer immunity and inflammation.75 ILC2s have been reported to block PD-1 via activation of tissue-specific cancer immunity.76 In addition, prophylactic TNF blockade dissociated efficacy and toxicity in anti-CTLA-4 and anti-PD-1 combined immunotherapy.77 Promising antitumor benefits can be obtained by combining anti-PD1/PD-L1 antibodies with other treatments of prostate cancer (Figure 2; Table 2).

Figure 2.

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Anti-PD-1/PD-L1 in combination with other therapies

Anti-PD-1/PD-L1 combined with other compounds exhibit effective antitumor effects, including RNS neutralizing agent, prophylactic TNF blockade, anti-RANKL, IL-15, Sigma1 inhibitor, CD73 blockade, nitroxoline, TGF-β blockade, GDF15, TH-302, A485, loss of ADAR1, androgen deprivation, TSAxCD28, antitumor vaccine, and chemoradiotherapy.

Table 2.

Combination of anti-PD-1/PD-L1 therapeutic strategy with other treatments

Treatments Anti-PD-1/PD-L1 Functions Reference
RNS neutralizing agent anti-PD-1 and anti-CTLA4 antibodies enhances anti-CRPC efficacy Feng et al.78
Prophylactic TNF blockade anti-PD-1/PD-L1 antibodies attenuates autoimmune adverse events and enhances immunotherapy efficacy Perez-Ruiz et al.77
Anti-RANKL PD-1/PD-L1 blockade therapy enhances the efficacy of immunotherapy and suppresses tumor growth Ahern et al.79
IL-15 anti-CTLA-4 and anti-PD-L1 antibodies reduces tumor growth rate and improves animal survival Yu et al.80
Sigma1 inhibitor PD-L1/PD-1 blockade regulates the tumor immune microenvironment Maher et al.81
CD73 blockade anti-CTLA-4 and anti-PD-1 antibodies enhances the anti-tumor effect of anti-CTLA-4 and anti-PD-1 Allard et al.82
Nitroxoline PD-1 blockade inhibits tumor growth and enhances PD-1 blockade effect Xu et al.83
TGF-β blockade anti-PD-L1 antibody provokes T cell penetration Mariathasan et al.72
GDF15 PD-1 antibody reduces tumor growth Husaini et al.84
TH-302 PD-1 blockade reduces cancer progression Jayaprakash et al.85
A485 anti-PD-L1 antibody exerts tumor attack function Liu et al.86
Loss of ADAR1 PD-1 blockade enhances the sensitivity to PD-1 blockade Ishizuka et al.74
Androgen deprivation PD-1 blockade strengthens the efficacy of checkpoint blockade Obradovic et al.,87 Benzon et al.,88 Yuan et al.,89 Graff et al.90
TSAxCD28 PD-1 blockade produces long-term anti-tumor immunity Waite et al.91
Antitumor vaccine PD-1/PD-L1 blockade promotes anti-tumor immune response Grenier et al.,92 Rekoske et al.,93 Simons et al.,94 Zhang et al.,95 Shi et al.,96 Fong et al.97
Chemoradiotherapy anti-PD-1/PD-L1 antibodies enhances efficacy of chemoradiotherapy Dudzinski et al.,98 Czernin et al.,99 Jin et al.,100 Truillet et al.101
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Pembrolizumab

A phase Ib nonrandom prostate cancer study on the anti-PD-1 inhibitor pembrolizumab found that pembrolizumab caused a long-lasting objective reaction in patients with advanced PD-L1-positive prostate cancer who had undergone a large amount of pretreatment.102 In these cancer patients, the objective response rate (ORR) was 17.4%, and the median duration of response was 13.5 months. The median progression-free survival (PFS) and overall survival were 3.5 and 7.9 months, respectively.102 Recently, a retrospective study reported that after receiving pembrolizumab for patients with mCRPC, 17% (8/48) of men had a PSA drop of ≥50%, among which 8% (4/48) of the PSA drop was ≥90%.103 Although the above results are very encouraging, there are some examples in the literature documenting that pembrolizumab in combination with other therapies has better antitumor activity.

RNS neutralizing agent

In a CRPC mouse model with prostate-specific deletion of PTEN, p53, and Smad4, CRPC was resistant to the treatment strategy of a combination of anti-PD-1 and anti-cytotoxic T lymphocyte-associated protein 4 (CTLA4) antibodies. These data established an innovative mechanism that can inactivate T cells due to protein nitrification induced by myeloid-derived suppressor cells (MDSCs); that is, when combined with reactive nitrogen species (RNS) neutralizing agent with immune checkpoint blockade (ICB) therapy, which contributes to enhancing anti-CRPC efficacy.78

Anti-RANKL

Receptor activator of NF-κB ligand (RANKL) is a member of the TNF superfamily.104 A previous study found that an anti-RANKL antibody in combination with an anti-PD-1 antibody inhibited tumor growth and alleviated ICI resistance in advanced cancer.105 Consistently, another study revealed that RANKL blockade increased the effect of PD1/PD-L1 blockade and anti-CTLA4 combination therapy, which upregulated the percentage of CD4+ and CD8+ T cells and promoted the production of IFN-γ and TNF.79 Treatment with anti-RANKL improved the antimetastatic activity of PD-1/PD-L1 blockade therapy and strengthened subcutaneous growth suppression in mouse prostate cancer models.79

IL-15

Yu et al.80 revealed that combination blockade of anti-CTLA-4 and anti-PD-L1 along with administration of IL-15 simultaneously increased the number of tumor-antigen-specific tetramer-positive CD8+ T cells, CD8+ T cell tumor lytic activity, and antigen-specific IFN-γ release; reduced the tumor growth rate; and improved animal survival compared with IL-15 alone. These phenomena suggested that triple combination therapy enhanced immune activity and increased antitumor effects in a prostate cancer model.80 These clinical trials suggested that anti-PD-1/PD-L1 inhibitors in combination with other ICIs or agents can obtain better efficacy than monotherapy.

Sigma1 modulator

Selecting the best drug candidates for treatment and determining the best drug sequence and drug combination are the key steps to obtaining the maximum antitumor effect. Sigma1, also called sigma-1 receptor, is a unique transmembrane molecule that is involved in diverse biological processes, such as neurodegeneration and cancer.106 In androgen-independent prostate cancer cells, the PD-L1 protein level was inhibited by sigma1 RNAi knockdown and sigma1 small-molecule inhibitors. A small-molecule sigma1 modulator can be used to modulate the expression level of PD-L1 in cancer cells and trigger the degradation of PD-L1 through selective autophagy, thereby preventing the expression of functional PD-L1 on the cell surface.81 These results indicated that a sigma1 modulator could be used as a new type of therapeutic drug in the PD-L1/PD-1 blocking strategy, which can regulate the tumor immune microenvironment.81

CD73 blockade

CD73, an extracellular nucleotidase, catabolizes extracellular adenosine triphosphate (ATP) into immunosuppressive adenosine, leading to a limiting immune response.107,108 Targeted blockade of CD73 can enhance the antitumor effect of anti-CTLA-4 and anti-PD-1 monoclonal antibodies on prostate cancer, providing a new treatment strategy for using ICIs.82

Nitroxoline

A study revealed that nitroxoline, a treatment for urinary tract infections approved by the FDA, showed antitumor effects in cancer patients.109 Recently, another investigation found that nitroxoline downregulates the expression of PD-L1 in prostate cancer cell lines and tumor tissues. In an orthotopic mouse model of prostate cancer, compared with nitroxoline or PD-1 block alone, the combination of nitroxoline and PD-1 block synergistically inhibited tumor growth, resulting in a decrease in tumor weight and biological luminescent tumor signal and a reduction in serum PSA levels, indicating that nitroxoline plus PD-1 block may be a promising treatment for prostate cancer patients.83

TGF-β blockade

TGF-β, a multifunctional cytokine, is related to a poor prognosis and plays an adverse role in various kinds of cancers by triggering immune escape, metastasis, angiogenesis, and EMT.70,71,110 A recent study revealed that TGF-β restricted T cell infiltration and inhibited antitumor immunity.72 The lack of an effective response in patients was related to the enrichment of TGF-β signaling in fibroblasts, so CD8+ T cells were excluded from the tumor parenchyma.72 Furthermore, they found that the combination of TGF-β blockade antibody with anti-PD-L1 provoked T cell penetration into tumors by inhibiting the TGF-β signaling pathway, which promoted antitumor immunity and retarded tumor progression.72

GDF15

Growth/differentiation factor-15 (GDF15) is a member of the TGF-β superfamily. It is an important hormone that modulates lipid and carbohydrate metabolism.111, 112, 113 In human cancer, GDF15 plays essential roles in angiogenesis, EMT, and drug resistance and acts as a target for cancer immunotherapy.112,114 Injecting GDF15 into TRAMP tumor mice in situ can reduce prostate tumor growth, while administration of an anti-PD-1 antibody can further reduce tumor growth. GDF15 overexpression or recombinant protein protects the growth of TRAMP tumors by regulating the antitumor immunity mediated by CD8+ T cells and enhances the efficacy of anti-PD-1 blockade.84

TH-302

TH-302, a hypoxia-activated prodrug, is used to reduce or eliminate hypoxia.115 Under hypoxic conditions, TH-302 was used to target cancer cells, reduce tumor drug resistance, and provide a new method for cancer therapy.116, 117, 118 In neuroendocrine prostate cancer, a higher level of hypoxia was shown in comparison with prostate adenocarcinoma, and tumor growth was decreased after treatment with the hypoxia-activated prodrug TH-302.119 Jayaprakash et al.85 discovered that combination therapy with TH-302 and PD-1 checkpoint blockade showed a minimal tumor burden. By this combination of hypoxia-prodrug and checkpoint blockade in spontaneous prostate tumors of TRAMP transgenic mice, an extension of survival was observed in a mouse model of aggressive prostate adenocarcinoma.85

p300/CBP inhibitor A485

One study reported that p300/CBP can be recruited to the CD274 promoter (encoding PD-L1) through the transcription factor IRF-1, which induces the acetylation of histone H3 on the CD274 promoter, and then promotes CD274 transcription.86 The researchers also found that the p300/CBP inhibitor A485 blocks this process and then cuts off the secretion of exosomal PD-L1 by blocking the transcription of CD274, which works in conjunction with anti-PD-L1 antibodies to reactivate the function of T cells, thereby exerting a tumor attack function.86 This study provides a strategy that could control exosomal PD-L1 levels, which leads to enhanced efficacy of PD-L1 blockade therapy in prostate cancer.

Androgen-deprivation therapy

PD-L1 overexpression is related to high androgen receptor positivity in prostate cancer patients.26,120 PD-L1 expression appears to be modestly increased through treatment with the luteinizing hormone releasing hormone (LHRH) antagonist degarelix alone, which is consistent with the phenomenon that cytokine secretion from infiltrating CD8+ T cells may lead to immune checkpoint upregulation.87 In a murine model of prostate cancer, androgen deprivation, local therapy with cryoablation, and PD-1 blockade constitute trimodal therapy, which has been shown to suppress tumor growth and extend mouse survival time compared to cryoablation combined with androgen-deprivation therapy (ADT) and strengthen the efficacy of checkpoint blockade.88 Recently, a phase I/II trial demonstrated that the combination of the anti-PD-1 drug nivolumab with ADT and high-dose-rate brachytherapy was well tolerated and improved immune-cell infiltration in prostate tumors.89 Another single-arm phase II study of 28 patients with mCRPC treated them with the second-generation androgen receptor inhibitor enzalutamide plus the PD-1 inhibitor pembrolizumab.90 Their objective responses were durable and complete, even without tumor PD-L1 expression or DNA repair defects in their tumors.90

TSAxCD28

Studies on mice and monkey models have demonstrated that a combination of the “costimulatory bispecifics” that crosslink TSA to CD28 (TSAxCD28) antibody and PD-1 blocking monoclonal antibody (mAb) with tumor-targeting immunotherapy can promote strong intratumoral T cell activation and produce long-term antitumor immunity in animal tumor models.91 Moreover, this combination approach is not limited to a specific cancer model and has a wide range of applications in combined immune therapy.91

Antitumor vaccine

Recent studies have shown that, similar to chemotherapy, cancer vaccination programs combined with immunotherapy may be effective in overcoming tumor immune evasion.92 After tumor-antigen-specific DNA vaccination, the expression of PD-L1 on circulating tumor cells (CTCs) is increased, and this upregulation of PD-L1 is related to the development of persistent T cell immunity and longer progression-free survival. These findings provide the benefit of combining anticancer vaccines with PD-1 blocking antibodies for the treatment of prostate cancer.93 When TRAMP mice were in the advanced stage of prostate cancer, by use of a novel virus-like particle (VLP) vaccine, anti-PD1 antibody, or combined immunotherapy for treatment, it was found that the VLP vaccine used alone or combined with the anti-PD1 antibody could significantly reduce the tumor burden compared with the anti-PD1 antibody alone.94 Sequential administration of anti-PD-1 and anti-Tim-3 antibodies can further improve the efficacy of anchored granulocyte-macrophage colony-stimulating factor (GM-CSF) vaccine therapy, and tumor regression was found in more than 60% of mouse models. The specific cytotoxic activity, proliferation, and secretion of CD8+ TILs were improved, and the production of tumor-promoting cytokines was decreased by this triple therapy. These results demonstrated that triple therapy could obtain an effective antitumor immune response in prostate cancer.95

In addition, the combined use of PD-1/PD-L1 blockers in GM-CSF vaccine therapy can significantly increase the population of CD4+ T cells, CD8+ T cells, and CD8+ IFN-γ+ T cells but does not increase the number of CD4+ Foxp3+ T cells or induce the highest IFN-γ production. Taken together, a combination of PD-1/PD-L1 blockers and streptavidin-GM-CSF (SA-GM-CSF) vaccines can effectively induce a strong and specific antitumor immune response against prostate cancer.96 On the other hand, sipuleucel-T (a cellular vaccine product targeting prostatic acid phosphatase) has been approved by the FDA for use in mCRPC. A study reported that the sipuleucel-T vaccine could increase prostate cancer immune infiltrate and create a useful environment for PD-1/PD-L1 blockade, indicating that the sipuleucel-T vaccine combined with PD-1/PD-L1 blockade may be a promising immunotherapy strategy.97

Anti-PD-1/PD-L1 combined with chemoradiotherapy

Radiotherapy

In addition to the abovementioned proposed strategies to enhance treatment efficacy, it is necessary to discuss chemoradiotherapy combined with anti-PD1/PD-L1 immunotherapy. In a mouse model of CRPC, the combination of PD-1 or PD-L1 immune checkpoint suppression with X-ray radiotherapy increased the median survival and reduced the mean graft volume. Then, flow cytometry and immunohistochemistry identified the number of CD8+ immune cells in transplants harvested at the peak of immunotherapy 2–3 weeks after the combination therapy, indicating that these phenomena may be in part mediated by CD8 T cells.98 In another study, prostate-specific membrane antigen (PSMA)-targeted radionuclide therapy (RNT) combined with PD-1 blockade prolonged the time to develop progression and reduced the tumor burden in a mouse model of prostate cancer, which suggested that the combination of RNT with PD-1 blockade immunotherapy could be a promising therapeutic approach for prostate cancer patients.99 Additionally, one study recently demonstrated that S249/T252 phosphorylated retinoblastoma protein (RB) was negatively correlated with PD-L1 expression in a variety of patient samples, including prostate cancer.100 RB-derived expression of S249/T252 phosphorylated mimetic peptide inhibits radiotherapy-induced upregulation of PD-L1 and enhances the treatment efficacy of in vivo radiotherapy. These findings revealed the tumor suppressor function of hyperphosphorylated RB in the inhibition of NF-κB activity and PD-L1 expression, indicating that the activity of RB can be exploited to overcome cancer immune tolerance associated with the current therapeutics, including radiotherapies and chemotherapies.100

Chemoradiotherapy

One study developed a new recombinant human IgG1 (C4), which can effectively bind to the extracellular epitopes on human and mouse PD-L1 in prostate cancer models and radiolabel the antibody with zirconium-89. Low levels of PD-L1 can be detected with immuno-positron emission tomography (immunoPET) using new recombinant human antibodies. High-sensitivity imaging can provide cancer patients with a more effective method to detect the expression of target antigens and improve the identification of patients who may benefit from cancer immunotherapy.101 These findings showed that the combination of anti-PD-1/PD-L1 therapy and chemoradiotherapy might achieve encouraging results, especially when combined with radiotherapy.

Conclusions

Treatments with monoclonal antibodies that block PD-1 or PD-L1 checkpoints have improved cancer immunotherapy. Recent investigations found that PD-L1 is a biomarker of the prognosis of prostate cancer patients treated with immunotherapies. Moreover, PD-1/PD-L1 blockade combined with other therapeutic methods represents a novel and promising treatment strategy that contributes to improving the treatment efficacy of prostate cancer. It is also necessary to search for ways to select the most appropriate treatment combination strategies to enhance the benefit of immunotherapy. It is important to note that primary clinical trials of PD-1 blockade in prostate cancer have failed, making immune checkpoint therapy for prostate cancer a challenge. The reasons for the failure might be complex, including the tumor microenvironment and adverse side effects such as liver and kidney toxicity. Therefore, many essential problems need to be explored in future investigations. For instance, are there other miRNAs or lncRNAs involved in PD-1/PD-L1 regulation? Do circular RNAs (circRNAs) regulate PD-1/PD-L1 expression in prostate cancer? Additionally, are there any other better treatment approaches in combination with anti-PD-1/PD-L1 antibodies to improve the efficacy of immunotherapy? Are there other upstream signaling pathways that affect the expression of PD-1/PD-L1? Does targeting these upstream factors of PD-1/PD-L1 improve the effect of immunotherapy? It is believed that these explorations will improve the therapeutic effect of PD-1/PD-L1 in the treatment of prostate cancer and provide new ideas for immunotherapy strategies.

Acknowledgments

Author contributions

Y.X., G.S., S.X., W.J., X.C., and M.C. searched literature regarding PD-1 and PD-L1 in prostate cancer. Y.X. made the figures. Y.X., X.H., and Z.W. wrote the manuscript. All authors read and approved the final manuscript.

Declaration of interests

The authors declare no competing interests.

Contributor Information

Xiaoli Hu, Email: wmuhuxiaoli2020@163.com.

Zhi-wei Wang, Email: zhiweichina@126.com.

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