The alveolar immune cell landscape is dysregulated in checkpoint inhibitor pneumonitis

支气管肺泡灌洗 免疫系统 淋巴细胞增多症 免疫学 肺炎 免疫疗法 过敏性肺炎 髓样 医学 T细胞 生物 癌症研究 内科学
作者
Karthik Suresh,Jarushka Naidoo,Qiong Zhong,Ye Xiong,Jennifer S. Mammen,Marcia Villegas de Flores,Laura C. Cappelli,Aanika Balaji,Tsvi Palmer,Patrick M. Forde,Valsamo Anagnostou,David S. Ettinger,Kristen A. Marrone,Ronan J. Kelly,Christine L. Hann,Benjamin Levy,Josephine Feliciano,Cheng Ting Lin,David Feller‐Kopman,Andrew D. Lerner,Hans C. Lee,Mājid Shafiq,Lonny Yarmus,Evan J. Lipson,Mark J. Soloski,Julie R. Brahmer,Sonye K. Danoff,Franco R. D’Alessio
出处
期刊:Journal of Clinical Investigation [American Society for Clinical Investigation]
卷期号:129 (10): 4305-4315 被引量:125
标识
DOI:10.1172/jci128654
摘要

Checkpoint inhibitor pneumonitis (CIP) is a highly morbid complication of immune checkpoint immunotherapy (ICI), one which precludes the continuation of ICI. Yet, the mechanistic underpinnings of CIP are unknown.To better understand the mechanism of lung injury in CIP, we prospectively collected bronchoalveolar lavage (BAL) samples in ICI-treated patients with (n=12) and without CIP (n=6), prior to initiation of first-line therapy for CIP (high dose corticosteroids. We analyzed BAL immune cell populations using a combination of traditional multicolor flow cytometry gating, unsupervised clustering analysis and BAL supernatant cytokine measurements.We found increased BAL lymphocytosis, predominantly CD4+ T cells, in CIP. Specifically, we observed increased numbers of BAL central memory T-cells (Tcm), evidence of Type I polarization, and decreased expression of CTLA-4 and PD-1 in BAL Tregs, suggesting both activation of pro-inflammatory subsets and an attenuated suppressive phenotype. CIP BAL myeloid immune populations displayed enhanced expression of IL-1β and decreased expression of counter-regulatory IL-1RA. We observed increased levels of T cell chemoattractants in the BAL supernatant, consistent with our pro-inflammatory, lymphocytic cellular landscape.We observe several immune cell subpopulations that are dysregulated in CIP, which may represent possible targets that could lead to therapeutics for this morbid immune related adverse event.
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