PO.IM02.05 · 免疫学
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
作者与单位
摘要 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).