Paucity of PD-L1 expression in prostate cancer: innate and adaptive immune resistance

Abstract

Background Primary prostate cancers are infiltrated with PD-1 expressing CD8+ T cells. However, in early clinical trials, men with mCRPC did not respond to PD-1 blockade as a monotherapy. One explanation for this unresponsiveness could be that prostate tumors generally do not express PD-L1, the primary ligand for PD-1. However, lack of PD-L1 expression in prostate cancer would be surprising, given that PTEN loss is relatively common in prostate cancer and several studies have shown that PTEN loss correlates with PD-L1 up-regulation - constituting a mechanism of innate immune resistance. This study tested whether prostate cancer cells were capable of expressing PD-L1, and whether the rare PD-L1 expression that occurs in human specimens correlates with PTEN loss. Methods Human prostate cancer cell lines were evaluated for PD-L1 expression and loss of PTEN by flow cytometry and western blotting, respectively. Immunohistochemical (IHC) staining for PTEN was correlated with PD-L1 IHC using a series of resected human prostate cancer samples. Results In vitro, many prostate cancer cell lines up-regulated PD-L1 expression in response to inflammatory cytokines, consistent with adaptive immune resistance. In these cell lines, no association between PTEN loss and PD-L1 expression was apparent. In primary prostate tumors, PD-L1 expression was rare, and was not associated with PTEN loss. Conclusions These studies show that some prostate cancer cell lines are capable of expressing PD-L1. However, in human prostate cancer, PTEN loss is not associated with PD-L1 expression, arguing against innate immune resistance as a mechanism that mitigates anti-tumor immune responses in this disease.

Treatment strategies for DNA repair-deficient prostate cancer

“…A signature defining a potential response to anti-PD-1 therapy has not been developed, such as quantifying and correlating PD-1/PD-L1 expression to response or associating response for patients with specific prior treatments. The data regarding expression of PD-1/PD-L1 in prostate cancer is conflicting [60, 61,62]. Furthermore, it is possible that therapy for prostate cancer (such as antiandrogens) results in relative immunosuppression [63] that theoretically may blunt anti-PD-1 response.…”

Immunoregulatory functions of PD-1/PD-L1 inhibitors and development of resistance to them

“…В свою очередь, низкоиммуногенные опухоли, такие, как опухоли подже-лудочной железы и простаты, несущие от 0,1 до 1 сома-тической мутации ДНК, в большей степени резистентны к анти-PD-1 терапии [3,41,42].…”

Epigenetic priming of both tumor and NK cells augments antibody-dependent cellular cytotoxicity elicited by the anti-PD-L1 antibody avelumab against multiple carcinoma cell types

“…1–5 Despite eliciting unprecedented clinical benefits for 20–50% of patients with diverse cancers, these agents still fail to benefit most patients with solid malignancies, including those with lung, prostate, ovarian, and triple-negative breast cancer. 6,7 Thus, there is an unmet clinical need to develop therapeutic strategies that can augment clinical responses to this class of immune checkpoint inhibitors across multiple solid malignancies.…”

“…1,6 In addition, previous research, mostly in melanoma and non-small cell lung (NSCL) cancer, strongly suggests that resistance to checkpoint blockade, including targeting the PD-1/PD-L1 axis, is highly associated with innate or acquired tumor defects in interferon (IFN)‒γ signaling and antigen processing and presentation pathways. 7–11 …”