小柯机器人

美国纽约大学Michele Pagano等研究人员合作发现，EMSY抑制同源重组修复和干扰素反应，从而促进肺癌的免疫逃逸。相关论文于2021年12月27日在线发表在《细胞》杂志上。

研究人员表明，KEAP1靶向EMSY进行泛素介导的降解，从而调节同源重组修复（HRR）和抗肿瘤免疫力。非小细胞肺癌（NSCLC）中KEAP1的缺失会诱发EMSY的稳定，产生BRCAness表型，即HRR缺陷和对PARP抑制剂的敏感性。缺陷的HRR导致了高的肿瘤突变负担，反过来，可能会促使先天免疫反应。

值得注意的是，EMSY的积累抑制了I型干扰素反应，损害了先天免疫信号，并促进了癌症免疫逃避。使用STING激动剂激活肿瘤微环境中的I型干扰素反应会导致先天和适应性免疫信号的激活，并损害KEAP1突变体肿瘤的生长。这些结果表明，靶向PARP和STING途径（单独或结合使用）是携带KEAP1改变的NSCLC患者的治疗策略。

据悉，携带KEAP1突变的NSCLC往往对免疫疗法有抵抗力。

附：英文原文

Title: EMSY inhibits homologous recombination repair and the interferon response, promoting lung cancer immune evasion

Author: Antonio Marzio, Emma Kurz, Jennifer M. Sahni, Giuseppe Di Feo, Joseph Puccini, Shaowen Jiang, Carolina Alcantara Hirsch, Arnaldo A. Arbini, Warren L. Wu, Harvey I. Pass, Dafna Bar-Sagi, Thales Papagiannakopoulos, Michele Pagano

Issue&Volume: 2021-12-27

Abstract: Non-small cell lung cancers (NSCLCs) harboring KEAP1 mutations are often resistant to immunotherapy. Here, we show that KEAP1 targetsEMSY for ubiquitin-mediated degradation to regulate homologous recombination repair(HRR) and anti-tumor immunity. Loss of KEAP1 in NSCLC induces stabilization of EMSY, producing a BRCAness phenotype, i.e., HRRdefects and sensitivity to PARP inhibitors. Defective HRR contributes to a high tumormutational burden that, in turn, is expected to prompt an innate immune response.Notably, EMSY accumulation suppresses the type I interferon response and impairs innateimmune signaling, fostering cancer immune evasion. Activation of the type I interferonresponse in the tumor microenvironment using a STING agonist results in the engagementof innate and adaptive immune signaling and impairs the growth of KEAP1-mutant tumors. Our results suggest that targeting PARP and STING pathways, individuallyor in combination, represents a therapeutic strategy in NSCLC patients harboring alterationsin KEAP1.

DOI: 10.1016/j.cell.2021.12.005

Source: https://www.cell.com/cell/fulltext/S0092-8674(21)01427-6