PO.IM02.05 · 免疫学

RBM10缺失通过非经典STING/NF-κB轴促进KRAS突变型非小细胞肺癌的免疫耐受和PD-1抑制剂耐药

RBM10 loss promotes KRAS -mutant non-small cell lung cancer immune tolerance and PD-1 inhibitor resistance via a non-canonical STING/ NF-κB axis

编号 6989 展板 1 时间 4/22 09:00–12:00 区域 Section 9 主讲 Minh Truong Do, PhD

分会场 Tumor-induced Immune Suppression

查看 PDF 下载 PDF 🔒 查看 / 下载完整 PDF 需登录并开通下载套餐 · 查看套餐 / 开通 AACR 官方页面

作者与单位 Authors & Affiliations

Minh Truong Do¹, Teng Zhou¹, Mhd Yousuf Yassouf¹, Richard Lee¹, Obada E. Ababneh¹, Yanhua Tian¹, Leticia B. Rodriguez¹, Jayanthi Gudikote¹, Haniel A. Araujo¹, Stephanie T. Schmidt², Jing Wang³, Frank R. Rojas Alvarez⁴, Luisa M. Solis Soto⁴, Marcelo V. Negrao¹, Alexandre Reuben¹, Don L. Gibbons¹, Jianjun Zhang¹, John V. Heymach¹, Ferdinandos Skoulidis¹

¹Thoracic and Head and Neck Medical Oncology, UT MD Anderson Cancer Center, Houston, TX,²Genomic Medicine and the Institute for Data Science in Oncology, UT MD Anderson Cancer Center, Houston, TX,³Bioinformatics and Computational Biology, UT MD Anderson Cancer Center, Houston, TX,⁴Translational Molecular Pathology, UT MD Anderson Cancer Center, Houston, TX

摘要 Abstract

中文摘要

RBM10编码一种参与调控可变剪接的蛋白，其功能缺失突变见于约10%的非鳞状NSCLC，并在携带KRAS激活突变的肿瘤中富集，然而关于RBM10失活如何促进肺癌进展或影响对标准治疗方案系统治疗的反应，人们知之甚少。在此，我们利用一种带有条件性RBM10缺失的新型基因工程小鼠模型，以及多个忠实重现RBM10缺陷型人肺腺癌的同基因同系移植模型，阐明了致癌性KRAS激活与RBM10缺失在NSCLC发病机制中的协同相互作用。我们发现，RBM10缺失通过促进形成一种耐受性的、富含髓系细胞的肿瘤免疫微环境（TIME），加速了KRAS突变型NSCLC的进展。从机制上讲，RBM10缺失促进了R-loop的积累和慢性DNA损伤信号，后者以不依赖cGAS的方式激活了非经典的TRAF6-STING通路，导致NF-κB持续激活。我们鉴定出了几种细胞因子和趋化因子——NF-κB信号的经典靶标，如IL-1beta、IL-6、TNFalpha和MCP-1，它们在RBM10缺陷型细胞中上调。这种NF-κB驱动的分泌组促进了一种炎性TIME的形成，其特征为抑制性髓系细胞亚群（最显著的是单核细胞和M2样巨噬细胞）的积累以及功能失调的肿瘤浸润淋巴细胞（TIL），从而促进免疫逃逸和癌症进展。此外，我们利用癌症基因组图谱（TCGA）中的人肺腺癌RNA-seq数据库，再次发现RBM10缺失与DNA损伤反应受损、HALLMARK_TNFA_SIGNALING_VIA_NF-κB上调以及M2巨噬细胞富集显著相关。引人注目的是，用抗CSF1R抗体靶向CSF1/CSF1R轴，在同基因免疫功能正常的模型中显著抑制了RBM10缺陷型肿瘤的生长，并与抗PD-1治疗协同促进肿瘤消退。总之，我们的研究结果揭示了RBM10失活在驱动KRAS突变型NSCLC免疫逃逸和PD-1抑制剂耐药中的一个新的关键作用，并提示通过共同靶向抑制性髓系细胞来改善癌症免疫治疗，为携带KRAS;RBM10共突变肿瘤的患者提供了一种潜在的治疗策略。

查看英文原文 English abstract

Loss-of-function mutations in RBM10 , encoding a protein involved in the regulation of alternative splicing, are observed in ~10% of non-squamous NSCLC and are enriched in tumors harboring activating mutations in KRAS , yet little is known about how RBM10 inactivation promotes lung cancer progression or influences response to standard-of-care systemic therapies. Here, we elucidated the cooperative interplay between oncogenic KRAS activation and RBM10 loss in NSCLC pathogenesis using a novel genetically engineered mouse model with conditional RBM10 deletion, as well as multiple isogenic syngeneic allograft models that faithfully recapitulate RBM10 -deficient human lung adenocarcinoma. We found that loss of RBM10 accelerates KRAS -mutant NSCLC progression by fostering the establishment of a tolerogenic, myeloid cell-rich tumor immune microenvironment (TIME). Mechanistically, RBM10 loss promoted R-loop accumulation and chronic DNA damage signaling that engaged the non-canonical TRAF6-STING pathway in a cGAS-independent manner, leading to sustained NF-κB activation. We identified several cytokines and chemokines, canonical targets of NF-κB signaling, such as IL-1beta, IL-6, TNFalpha, and MCP-1, that were upregulated in RBM10 -deficient cells. This NF-κB-driven secretome promoted the development of an inflamed, TIME characterized by accumulation of suppressive myeloid cell subsets - most notably monocytes and M2-like macrophages, and dysfunctional tumor infiltrating lymphocytes (TILs) thereby fostering immune evasion and cancer progression. Furthermore, we exploited the RNA-seq database of human lung adenocarcinoma from The Cancer Genome Atlas (TCGA) and again found that RBM10 loss was significantly linked to impaired DNA damage response, upregulation of the HALLMARK_TNFA_SIGNALING_VIA_NF-κB, and enrichment of M2-macrophages. Strikingly, targeting the CSF1/CSF1R axis with an anti-CSF1R antibody significantly curtailed the growth of RBM10 -deficient tumors in syngeneic immunocompetent models and synergized with anti-PD-1 therapy to promote tumor regression. In conclusion, our findings uncovered a novel critical role of RBM10 inactivation in driving immune escape and PD-1 inhibitor resistance in KRAS -mutant NSCLC and suggest a potential therapeutic strategy by co-targeting suppressive myeloid cells to improve cancer immunotherapy for patients bearing KRAS;RBM10 co-mutated tumors.

利益披露 Disclosure

M. Do, None.. T. Zhou, None.. M. Yassouf, None.. R. Lee, None.. O. Ababneh, None.. Y. Tian, None.. L. Rodriguez, None.. J. Gudikote, None.. H. Araujo, None.. S. Schmidt, None.. J. Wang, None.. F. Rojas Alvarez, None.. L. Solis Soto, None. M. Negrao, Genentech, Sanofi, Pfizer, Lilly, AstraZeneca, BMS Consulting or Advisory board. OncLive, Ideology, BIO Brasil, Medscape, DAVA Oncology, Targeted Oncology Speaker's Bureau. Lilly, Mirati, BMS, Novartis, Alaunos, AstraZeneca, Pfizer, Genentech, Navire, Frontier Research Funding. Ideology, DAVA Oncology, Targeted Oncology Travel, accommodation, Expenses. ApotheCom, Ashfield Healthcare Writing Support. A. Reuben, None. D. Gibbons, Menarini Ricerche, Onconova, Aktis Oncology and Eli Lilly Served on scientific advisory committees. Ideology Health received honoraria for presentations. NGM Biopharmaceuticals, Boehringer Ingelheim, Eli Lilly and Mirati/Bristol-Myers Squibb received research support. J. Zhang, Helius, Johnson and Johnson, Merck, Novartis, Summit research funding. AstraZeneca, Catalyst, GenePlus, Helius, Hengrui, Innovent, Johnson and Johnson, Novartis, Oncohost, Takeda and Varian personal fees. J. Heymach, 23andMe, AstraZeneca, Bayer, BioNTech AG, BI, BMS, DAVA Oncology, EMD Serono, IDEOlogy Health, Intellisphere, InxMed (Hong Kong) Limited, Janssen Pharmaceuticals, Jazz Pharmaceuticals, ModeX, Advisory Committees. OncoHost, Ottimo Pharma, Regeneron Pharmaceuticals, Remunity Therapeutics, Synthekine Advisory Committees. Clinical Care Targeted Communications (11/21/25), Physicians Education Resource (PER) Speaking Events. AstraZeneca, Boehringer-Ingelheim, Mirati, Bristol-Myers Squibb, Takeda, Taiho Research Support. Tenaci-T Therapeutics Business Ownership. Spectrum Royalties and licensing fees. F. Skoulidis, Amgen Inc., Revolution Medicines, Novartis, BridgeBio, Beigene, BergenBio, AstraZeneca, Guardant Health, Calithera Biosciences, Tango Therapeutics, Merck Sharp & Dohme, Roche, Novocure, Consulting. Hookipa Pharma, Regeneron, Turning Point Therapeutics, BMS, Eli Lilly Consulting. AstraZeneca, Amgen, ESMO, AACR, IASLC, Japanese Lung Cancer Society, Medscape LLC, Intellisphere LLC, VSPO McGill Université de Montreal Honoraria/Lecture fees. MJH Life Science, IDEOlogy Health, MI&T, PER LLC, CURIO LLC, DAVA Oncology, BMS and RV Mais Promocao Eventos LTDS Honoraria/Lecture fees. DAVA Oncology, Tango Therapeutics, AstraZeneca Pharmaceuticals, and Amgen Inc., BMS, Revolution Medicines, AACR, IASLC, MJH Life Sciences, IDEOlogy Health, MI&T, PER LLC, CURIO LLC Fees for travel, food and beverage. BioNTech SE and Moderna Inc. (past) Stock or stock options. Amgen, Revolution Medicines, Mirati Therapeutics, Merck & Co., and Novartis Research grants (to institution). Pfizer Study Chair funds (to institution). Roche, Novartis, Almmune Consulting fees (spouse).

← 返回 AACR 2026 检索