小柯机器人

2022年12月14日，《自然》杂志在线发表了美国纪念斯隆-凯特琳癌症中心Sohrab P. Shah等研究人员的合作成果，这项研究发现，卵巢癌的突变过程驱动特定部位的免疫逃避。

研究人员对42名治疗无效的高级别浆液性卵巢癌（HGSOC）患者的160个肿瘤部位进行了全基因组测序、单细胞RNA测序、数字组织病理学和多重免疫荧光的综合分析。同源重组缺陷的HRD-Dup（BRCA1突变样）和HRD-Del（BRCA2突变样）肿瘤存在炎症信号和持续的免疫抑制，这反映在HLA多样性的丧失和肿瘤被高度分化的功能失调的CD8⁺T细胞浸润。相比之下，折返倒置的肿瘤表现出免疫抑制性TGFβ信号的升高和免疫排斥，主要是初始/干细胞和记忆T细胞。表型状态的关联是特定于解剖部位的，这突出了附件肿瘤和远端腹膜病灶之间的组成、拓扑学和功能差异。

这些研究结果表明，解剖学部位和突变过程是HGSOC演化表型分歧和免疫抵抗机制的决定因素。这项研究提供了一个多组学细胞表型数据基础，这能够促进开发和解释未来的个性化免疫治疗方法和早期检测研究。

据悉，HGSOC是一种典型的基因组不稳定的癌症，具有明显的突变过程、肿瘤异质性和腹膜内扩散。免疫疗法对HGSOC的疗效有限，这突出了评估突变过程和肿瘤病灶的解剖部位如何决定肿瘤微环境的免疫状态的需求没有得到满足。

附：英文原文

Title: Ovarian cancer mutational processes drive site-specific immune evasion

Author: Vzquez-Garca, Ignacio, Uhlitz, Florian, Ceglia, Nicholas, Lim, Jamie L. P., Wu, Michelle, Mohibullah, Neeman, Niyazov, Juliana, Ruiz, Arvin Eric B., Boehm, Kevin M., Bojilova, Viktoria, Fong, Christopher J., Funnell, Tyler, Grewal, Diljot, Havasov, Eliyahu, Leung, Samantha, Pasha, Arfath, Patel, Druv M., Pourmaleki, Maryam, Rusk, Nicole, Shi, Hongyu, Vanguri, Rami, Williams, Marc J., Zhang, Allen W., Broach, Vance, Chi, Dennis S., Da Cruz Paula, Arnaud, Gardner, Ginger J., Kim, Sarah H., Lennon, Matthew, Long Roche, Kara, Sonoda, Yukio, Zivanovic, Oliver, Kundra, Ritika, Viale, Agnes, Derakhshan, Fatemeh N., Geneslaw, Luke, Issa Bhaloo, Shirin, Maroldi, Ana, Nunez, Rahelly, Pareja, Fresia, Stylianou, Anthe, Vahdatinia, Mahsa, Bykov, Yonina, Grisham, Rachel N., Liu, Ying L., Lakhman, Yulia, Nikolovski, Ines, Kelly, Daniel, Gao, Jianjiong, Schietinger, Andrea, Hollmann, Travis J., Bakhoum, Samuel F., Soslow, Robert A., Ellenson, Lora H., Abu-Rustum, Nadeem R., Aghajanian, Carol, Friedman, Claire F., McPherson, Andrew, Weigelt, Britta, Zamarin, Dmitriy, Shah, Sohrab P.

Issue&Volume: 2022-12-14

Abstract: High-grade serous ovarian cancer (HGSOC) is an archetypal cancer of genomic instability1,2,3,4 patterned by distinct mutational processes5,6, tumour heterogeneity7,8,9 and intraperitoneal spread7,8,10. Immunotherapies have had limited efficacy in HGSOC11,12,13, highlighting an unmet need to assess how mutational processes and the anatomical sites of tumour foci determine the immunological states of the tumour microenvironment. Here we carried out an integrative analysis of whole-genome sequencing, single-cell RNA sequencing, digital histopathology and multiplexed immunofluorescence of 160 tumour sites from 42 treatment-naive patients with HGSOC. Homologous recombination-deficient HRD-Dup (BRCA1 mutant-like) and HRD-Del (BRCA2 mutant-like) tumours harboured inflammatory signalling and ongoing immunoediting, reflected in loss of HLA diversity and tumour infiltration with highly differentiated dysfunctional CD8+ T cells. By contrast, foldback-inversion-bearing tumours exhibited elevated immunosuppressive TGFβ signalling and immune exclusion, with predominantly naive/stem-like and memory T cells. Phenotypic state associations were specific to anatomical sites, highlighting compositional, topological and functional differences between adnexal tumours and distal peritoneal foci. Our findings implicate anatomical sites and mutational processes as determinants of evolutionary phenotypic divergence and immune resistance mechanisms in HGSOC. Our study provides a multi-omic cellular phenotype data substrate from which to develop and interpret future personalized immunotherapeutic approaches and early detection research.

DOI: 10.1038/s41586-022-05496-1

Source: https://www.nature.com/articles/s41586-022-05496-1

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