The alveolar immune cell landscape is dysregulated in checkpoint inhibitor pneumonitis

Karthik Suresh, Jarushka Naidoo, Qiong Zhong, Ye Xiong, Jennifer Mammen, Marcia Villegas De Flores, Laura 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 L. Feliciano, Cheng Ting Lin, David Feller-Kopman, Andrew D. LernerHans Lee, Majid Shafiq, Lonny Yarmus, Evan J. Lipson, Mark Soloski, Julie R. Brahmer, Sonye K. Danoff, Franco D'Alessio

Research output: Contribution to journalArticlepeer-review

28 Scopus citations


BACKGROUND. 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. METHODS. 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 initiating 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. RESULTS. We found increased BAL lymphocytosis, predominantly CD4+ T cells, in patients with CIP. Specifically, we observed increased numbers of BAL central memory T cells, evidence of type I polarization, and decreased expression of cytotoxic T lymphocyte-associated protein 4 and programmed cell death protein 1 in BAL Tregs, suggesting both activation of proinflammatory subsets and an attenuated suppressive phenotype. CIP BAL myeloid immune populations displayed enhanced expression of IL-1β and decreased expression of counterregulatory interleukin-1 receptor antagonist. We observed increased levels of T-cell chemoattractants in the BAL supernatant, consistent with our proinflammatory, lymphocytic cellular landscape. CONCLUSION. 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.

Original languageEnglish (US)
Pages (from-to)4305-4315
Number of pages11
JournalJournal of Clinical Investigation
Issue number10
StatePublished - Oct 1 2019

ASJC Scopus subject areas

  • General Medicine


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