Purpose: A subset of primary prostate cancer expresses programmed death-ligand 1 (PD-L1), but whether they have a unique tumor immune microenvironment or genomic features is unclear. Experimental Design: We selected PD-L1–positive high-grade and/or high-risk primary prostate cancer, characterized tumor-infiltrating lymphocytes with multiplex immunofluorescence, and identified genomic alterations in immunogenic and nonimmunogenic tumor foci. Results: One quarter of aggressive localized prostate cancer cases (29/115) had tumor PD-L1 expression more than 5%. This correlated with increased density of CD8+ T cells, a large fraction coexpressing PD-1, versus absent PD-1 expression on sparse CD8 T cells in unselected cases. Most CD8+PD-1+ cells did not express terminal exhaustion markers (TIM3 or LAG3), while a subset expressed TCF1. Consistent with these CD8+PD-1+TCF1+ cells being progenitors, they were found in antigen-presenting cell niches in close proximity to MHC-II+ cells. CD8 T-cell density in immunogenic prostate cancer and renal cell carcinoma (RCC) was nearly identical. Shallow RB1 and BRCA2 losses, and deep deletions of CHD1 , were prevalent, the latter being strongly associated with a dendritic cell gene set in The Cancer Genome Atlas. Tumor mutation burden was variable; neither high microsatellite instability nor CDK12 alterations were present. Conclusions: A subset of localized prostate cancer is immunogenic, manifested by PD-L1 expression and CD8+ T-cell content comparable with RCC. The CD8+ T cells include effector cells and exhausted progenitor cells, which may be expanded by immune checkpoint inhibitors (ICI). Genomic losses of RB1, BRCA2 , and CHD1 may be drivers of this phenotype. These findings indicate that immunotherapies may be effective in biomarker-selected subpopulations of patients with localized prostate cancer. This article is featured in Highlights of This Issue, [p. 4665][1] [1]: /lookup/volpage/27/4665?iss=17

中文翻译：

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局限性前列腺癌的一个子集显示出与关键抑癌基因缺失相关的免疫原性表型

目的：原发性前列腺癌的一个子集表达程序性死亡配体 1 (PD-L1)，但它们是否具有独特的肿瘤免疫微环境或基因组特征尚不清楚。实验设计：我们选择了 PD-L1 阳性的高级别和/或高危原发性前列腺癌，用多重免疫荧光表征肿瘤浸润淋巴细胞，并鉴定了免疫原性和非免疫原性肿瘤病灶的基因组改变。结果：四分之一的侵袭性局限性前列腺癌病例 (29/115) 的肿瘤 PD-L1 表达超过 5%。这与 CD8+ T 细胞密度增加相关，其中很大一部分共表达 PD-1，而在未选择的病例中，稀疏 CD8 T 细胞上没有 PD-1 表达。大多数 CD8+PD-1+ 细胞不表达终末衰竭标志物（TIM3 或 LAG3），而一部分表达 TCF1。与这些 CD8+PD-1+TCF1+ 细胞是祖细胞一致，它们被发现在靠近 MHC-II+ 细胞的抗原呈递细胞壁龛中。免疫原性前列腺癌和肾细胞癌 (RCC) 中的 CD8 T 细胞密度几乎相同。RB1 和 BRCA2 的浅层丢失以及 CHD1 的深度缺失很普遍，后者与癌症基因组图谱中的树突状细胞基因集密切相关。肿瘤突变负荷是可变的；既不存在高微卫星不稳定性也不存在 CDK12 改变。结论：局限性前列腺癌的一个子集具有免疫原性，表现为与 RCC 相当的 PD-L1 表达和 CD8+ T 细胞含量。CD8+ T 细胞包括效应细胞和耗尽的祖细胞，它们可以通过免疫检查点抑制剂 (ICI) 进行扩增。RB1、BRCA2、和 CHD1 可能是这种表型的驱动因素。这些发现表明，免疫疗法可能对局限性前列腺癌患者的生物标志物选择亚群有效。这篇文章刊登在本期要闻中，[p。4665][1][1]:/lookup/volpage/27/4665?iss=17