Prostate cancer cells synergistically defend against CD8⁺ T cells by secreting exosomal PD‐L1

Abstract

BackgroundMetastatic castration‐resistant prostate cancer (mCRPC) remains fatal and incurable, despite a variety of treatments that can delay disease progression and prolong life. Immune checkpoint therapy is a promising treatment. However, emerging evidence suggests that exosomal programmed necrosis ligand 1 (PD‐L1) directly binds to PD‐1 on the surface of T cells in the drain lineage lymph nodes or neutralizes administered PD‐L1 antibodies, resulting in poor response to anti‐PD‐L1 therapy in mCRPC.Materials and MethodsWestern blotting and immunofluorescence were performed to compare PD‐L1 levels in exosomes derived from different prostate cancer cells. PC3 cells were subcutaneously injected into nude mice, and then ELISA assay was used to detect human specific PD‐L1 in exosomes purified from mouse serum. The function of CD8+ T cells was detected by T cell mediated tumor cell killing assay and FACS analysis. A subcutaneous xenograft model was established using mouse prostate cancer cell RM1, exosomes with or without PD‐L1 were injected every 3 days, and then tumor size and weight were analyzed to evaluate the effect of exosomal PD‐L1.ResultsHerein, we found that exosomal‐PD‐L1 was taken up by tumor cells expressing low levels of PD‐L1, thereby protecting them from T‐cell killing. Higher levels of PD‐L1 were detected in exosomes derived from the highly malignant prostate cancer PC3 and DU145 cell lines. Moreover, exosomal PD‐L1 was taken up by the PD‐L1‐low‐expressing LNCaP cell line and inhibited the killing function of CD8‐T cells on tumor cells. The growth rate of RM1‐derived subcutaneous tumors was decreased after knockdown of PD‐L1 in tumor cells, whereas the growth rate recovered following exosomal PD‐L1 tail vein injection. Furthermore, in the serum of mice with PCa subcutaneous tumors, PD‐L1 was mainly present on exosomes.ConclusionIn summary, tumor cells share PD‐L1 synergistically against T cells through exosomes. Inhibition of exosome secretion or prevention of PD‐L1 sorting into exosomes may improve the therapeutic response of prostate tumors to anti‐PD‐L1 therapy.

Extracellular vesicles and prostate cancer management: a narrative review

“…Hence, selective removal of cancer-derived EVs via specific HER2 targeting will be an exceptionally promising approach for cancer treatment. Additionally, in PCa, as we referred above, PD-L1 on EVs may contribute to resistance to immunotherapy ( 60 , 61 ), thus, targeting PD-L1 positive EVs might be a good approach for PCa treatment.…”

“…In a syngeneic PCa model, resistance to anti-PD-L1 therapy appeared to be triggered by PD-L1, and therefore targeting PD-L1 might be a valuable therapeutic strategy ( 60 ). Li et al found that PD-L1 was transferred via EVs from PCa cells expressing high levels of PD-L1 to PCa cells expressing lower levels, thus aiding the ability of PCa to evade immune cells ( 61 ) ( Figure 3D ).…”

TLR9 Monotherapy in Immune-Competent Mice Suppresses Orthotopic Prostate Tumor Development

“…Prostate tumors often harbor a “cold” immunosuppressive tumor microenvironment and immunotherapies to overcome the multiple mechanisms of immuno-resistance are being trialed [ 50 ]. Recent insights into the immune profile of prostate tumors reveal a microenvironment rich in immunosuppressive myeloid cells as well as T-cell exhaustion signatures, such as increased PD-1 or PD-L1 [ 51 , 52 ]. As such, anti-PD-1 immunotherapy was able to improve T-cell effector activity and reduce prostate tumor development, further highlighting the immunosuppressive ability of tumor-infiltrating lymphocytes in the pathogenesis of prostate tumors [ 53 , 54 ].…”