白细胞介素12
CD40
肿瘤微环境
树突状细胞
免疫疗法
免疫系统
癌症免疫疗法
髓样
癌症研究
启动(农业)
免疫学
T细胞
获得性免疫系统
免疫检查点
生物
细胞毒性T细胞
生物化学
植物
发芽
体外
作者
Irina Krykbaeva,Kate Bridges,William Damsky,Gabriela A. Pizzurro,Amanda F. Alexander,Meaghan K. McGeary,Koonam Park,Viswanathan Muthusamy,Jim E. Eyles,Nadia Luheshi,Noel Turner,Sarah A. Weiss,Kelly Olino,Stefanie Kaech,Harriet M. Kluger,Kathryn Miller‐Jensen,Marcus W. Bosenberg
出处
期刊:Cancer immunology research
[American Association for Cancer Research]
日期:2023-07-21
卷期号:11 (10): 1332-1350
标识
DOI:10.1158/2326-6066.cir-22-0699
摘要
Abstract Checkpoint inhibitors have revolutionized cancer treatment, but resistance remains a significant clinical challenge. Myeloid cells within the tumor microenvironment can modulate checkpoint resistance by either supporting or suppressing adaptive immune responses. Using an anti–PD-1–resistant mouse melanoma model, we show that targeting the myeloid compartment via CD40 activation and CSF1R blockade in combination with anti–PD-1 results in complete tumor regression in a majority of mice. This triple therapy combination was primarily CD40 agonist-driven in the first 24 hours after therapy and showed a similar systemic cytokine profile in human patients as was seen in mice. Functional single-cell cytokine secretion profiling of dendritic cells (DC) using a novel microwell assay identified a CCL22+CCL5+ IL12-secreting DC subset as important early-stage effectors of triple therapy. CD4+ and CD8+ T cells are both critical effectors of treatment, and systems analysis of single-cell RNA sequencing data supported a role for DC-secreted IL12 in priming T-cell activation and recruitment. Finally, we showed that treatment with a novel IL12 mRNA therapeutic alone was sufficient to overcome PD-1 resistance and cause tumor regression. Overall, we conclude that combining myeloid-based innate immune activation and enhancement of adaptive immunity is a viable strategy to overcome anti–PD-1 resistance.
科研通智能强力驱动
Strongly Powered by AbleSci AI