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.FUNDING NIH, Department of Defense, and the Bloomberg~Kimmel Institute for Cancer Immunotherapy.
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. Lerner, Hans Lee, Majid Shafiq, Lonny Yarmus, Evan J. Lipson, Mark Soloski, Julie R. Brahmer, Sonye K. Danoff, Franco D’Alessio
Guidelines: The Editorial Board will only consider letters that we deem relevant and of interest to our readers. We will not post data that have not been subjected to peer review, nor will we post letters that are essentially a reiteration of another letter. We reserve the right to edit any letter for length, content, and clarity. Authors will be notified by e-mail if their letters were accepted. No appeals will be considered.
Specific requirements: All letters must be 400 words or fewer. You may enter the letter as plain text or HTML. The author's name and e-mail address are required, and will be posted with the letter. All possible conflicts of interest must be noted, even if they are not posted. If you wish to include a figure (keep in mind that non-peer-reviewed data will not be posted), please contact the editors directly at email@example.com.