Department of Medicine, Laura & Isaac Perlmutter Cancer Center, NYU Langone Health, New York, New York, USA.
Department of Medicine, Manhattan Campus, VA NY Harbor Health Care System, New York, New York, USA.
Prostate. 2023 Jun;83(9):840-849. doi: 10.1002/pros.24524. Epub 2023 Mar 29.
Evading immune surveillance is a hallmark for the development of multiple cancer types. Whether immune evasion contributes to the pathogenesis of high-grade prostate cancer (HGPCa) remains an area of active inquiry.
Through single-cell RNA sequencing and multicolor flow cytometry of freshly isolated prostatectomy specimens and matched peripheral blood, we aimed to characterize the tumor immune microenvironment (TME) of localized prostate cancer (PCa), including HGPCa and low-grade prostate cancer (LGPCa).
HGPCa are highly infiltrated by exhausted CD8 T cells, myeloid cells, and regulatory T cells (TRegs). These HGPCa-infiltrating CD8 T cells expressed high levels of exhaustion markers including TIM3, TOX, TCF7, PD-1, CTLA4, TIGIT, and CXCL13. By contrast, a high ratio of activated CD8 effector T cells relative to TRegs and myeloid cells infiltrate the TME of LGPCa. HGPCa CD8 tumor-infiltrating lymphocytes (TILs) expressed more androgen receptor and prostate-specific membran antigen yet less prostate-specific antigen than the LGPCa CD8 TILs. The PCa TME was infiltrated by macrophages but these did not clearly cluster by M1 and M2 markers.
Our study reveals a suppressive TME with high levels of CD8 T cell exhaustion in localized PCa, a finding enriched in HGPCa relative to LGPCa. These studies suggest a possible link between the clinical-pathologic risk of PCa and the associated TME. Our results have implications for our understanding of the immunologic mechanisms of PCa pathogenesis and the implementation of immunotherapy for localized PCa.
逃避免疫监视是多种癌症发展的标志。免疫逃避是否有助于高级别前列腺癌（HGPCa）的发病机制仍然是一个活跃的研究领域。
通过对新鲜分离的前列腺切除术标本和匹配的外周血进行单细胞 RNA 测序和多色流式细胞术，我们旨在描述局部前列腺癌（PCa）的肿瘤免疫微环境（TME），包括 HGPCa 和低级别前列腺癌（LGPCa）。
HGPCa 被耗尽的 CD8 T 细胞、髓样细胞和调节性 T 细胞（TRegs）高度浸润。这些 HGPCa 浸润的 CD8 T 细胞表达高水平的衰竭标志物，包括 TIM3、TOX、TCF7、PD-1、CTLA4、TIGIT 和 CXCL13。相比之下，高比例的活化 CD8 效应 T 细胞相对于 TRegs 和髓样细胞浸润 LGPCa 的 TME。HGPCa CD8 肿瘤浸润淋巴细胞（TIL）表达的雄激素受体和前列腺特异性膜抗原多于 LGPCa CD8 TIL，但前列腺特异性抗原较少。PCa TME 浸润巨噬细胞，但这些巨噬细胞没有明显根据 M1 和 M2 标志物聚类。
我们的研究揭示了局部 PCa 中存在高水平 CD8 T 细胞衰竭的抑制性 TME，在 HGPCa 中比 LGPCa 更为丰富。这些研究表明 PCa 的临床病理风险与相关 TME 之间可能存在联系。我们的研究结果对我们理解 PCa 发病机制的免疫机制和实施局部 PCa 的免疫治疗具有重要意义。
