美国哈佛医学院Toni K. Choueiri、Sachet A. Shukla、Catherine J. Wu等研究人员合作发现，体细胞改变和免疫浸润的相互作用调节晚期透明细胞肾细胞癌（ccRCC）对PD-1阻断的反应。2020年5月29日，《自然—医学》杂志在线发表了这项成果。

研究人员通过全外显子组和RNA测序，并结合免疫荧光分析，对参与PD-1阻断治疗前瞻性临床试验中ccRCC晚期患者的592例肿瘤进行了分析，以揭示治疗反应的免疫基因组决定因素。尽管常规的基因组标记（例如肿瘤突变负荷和新抗原负荷）以及CD8⁺T细胞浸润程度与临床反应无关，但研究人员发现了许多与反应或对PD-1阻断有关的染色体改变。

这些晚期ccRCC肿瘤高度浸润CD8⁺T细胞，只有27％具有未浸润的表型。这些分析表明，与未浸润的肿瘤相比，浸润的肿瘤耗尽了有利的PBRM1突变，并富集了不利的9p21.3染色体丢失，从而证明了免疫表型与体细胞改变的相互作用如何影响治疗效果。

据了解，PD-1阻断已改变了晚期ccRCC的临床治疗，但PD-1应答的驱动因素和耐药因素仍未完全阐明。

附：英文原文

Title: Interplay of somatic alterations and immune infiltration modulates response to PD-1 blockade in advanced clear cell renal cell carcinoma

Author: David A. Braun, Yue Hou, Ziad Bakouny, Miriam Ficial, Miriam Sant Angelo, Juliet Forman, Petra Ross-Macdonald, Ashton C. Berger, Opeyemi A. Jegede, Liudmilla Elagina, John Steinharter, Maxine Sun, Megan Wind-Rotolo, Jean-Christophe Pignon, Andrew D. Cherniack, Lee Lichtenstein, Donna Neuberg, Paul Catalano, Gordon J. Freeman, Arlene H. Sharpe, David F. McDermott, Eliezer M. Van Allen, Sabina Signoretti, Catherine J. Wu, Sachet A. Shukla, Toni K. Choueiri

Issue&Volume: 2020-05-29

Abstract: PD-1 blockade has transformed the management of advanced clear cell renal cell carcinoma (ccRCC), but the drivers and resistors of the PD-1 response remain incompletely elucidated. Here, we analyzed 592 tumors from patients with advanced ccRCC enrolled in prospective clinical trials of treatment with PD-1 blockade by whole-exome and RNA sequencing, integrated with immunofluorescence analysis, to uncover the immunogenomic determinants of the therapeutic response. Although conventional genomic markers (such as tumor mutation burden and neoantigen load) and the degree of CD8+ Tcell infiltration were not associated with clinical response, we discovered numerous chromosomal alterations associated with response or resistance to PD-1 blockade. These advanced ccRCC tumors were highly CD8+ Tcell infiltrated, with only 27% having a non-infiltrated phenotype. Our analysis revealed that infiltrated tumors are depleted of favorable PBRM1 mutations and enriched for unfavorable chromosomal losses of 9p21.3, as compared with non-infiltrated tumors, demonstrating how the potential interplay of immunophenotypes with somatic alterations impacts therapeutic efficacy.

DOI: 10.1038/s41591-020-0839-y

Source: https://www.nature.com/articles/s41591-020-0839-y