Abstract：
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.
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.
摘要：
背景：逃避免疫监视是多种癌症类型发展的标志。免疫逃避是否有助于高级别前列腺癌（HGPCa）的发病机理仍然是一个活跃的研究领域。
方法：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，我们旨在表征局部前列腺癌（PCa）的肿瘤免疫微环境（TME），包括HGPCa和低度前列腺癌（LGPCa）。
结果：HGPCa被耗尽的CD8+T细胞高度浸润，骨髓细胞，和调节性T细胞(TRegs)。这些HGPCa浸润性CD8+T细胞表达高水平的耗竭标志物，包括TIM3，TOX，TCF7,PD-1,CTLA4,TIGIT,和CXCL13。相比之下,活化的CD8+效应T细胞相对于TReg和骨髓细胞的高比例渗入LGPCa的TME。HGPCaCD8肿瘤浸润淋巴细胞（TIL）比LGPCaCD8TIL表达更多的雄激素受体和前列腺特异性膜抗原，但前列腺特异性抗原更少。PCaTME被巨噬细胞浸润，但这些并没有明显被M1和M2标记聚集。
结论：我们的研究揭示了在局部PCa中具有高水平CD8+T细胞耗竭的抑制性TME，相对于LGPCa，富含HGPCa的发现。这些研究表明PCa的临床病理风险与相关的TME之间可能存在联系。我们的结果对我们了解PCa发病机理的免疫机制以及对局部PCa的免疫治疗的实施具有重要意义。
方法：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，我们旨在表征局部前列腺癌（PCa）的肿瘤免疫微环境（TME），包括HGPCa和低度前列腺癌（LGPCa）。
结果：HGPCa被耗尽的CD8+T细胞高度浸润，骨髓细胞，和调节性T细胞(TRegs)。这些HGPCa浸润性CD8+T细胞表达高水平的耗竭标志物，包括TIM3，TOX，TCF7,PD-1,CTLA4,TIGIT,和CXCL13。相比之下,活化的CD8+效应T细胞相对于TReg和骨髓细胞的高比例渗入LGPCa的TME。HGPCaCD8肿瘤浸润淋巴细胞（TIL）比LGPCaCD8TIL表达更多的雄激素受体和前列腺特异性膜抗原，但前列腺特异性抗原更少。PCaTME被巨噬细胞浸润，但这些并没有明显被M1和M2标记聚集。
结论：我们的研究揭示了在局部PCa中具有高水平CD8+T细胞耗竭的抑制性TME，相对于LGPCa，富含HGPCa的发现。这些研究表明PCa的临床病理风险与相关的TME之间可能存在联系。我们的结果对我们了解PCa发病机理的免疫机制以及对局部PCa的免疫治疗的实施具有重要意义。
