Uncovering the immune mechanisms underlying the emergence of immunotherapy-induced pneumonitis in lung cancer patients.

Abstract

The clinical application of checkpoint inhibitors in lung cancer has been impeded by the emergence of immune-related adverse effects, such as pneumonitis. To date, the precise immune pathogenesis of immune checkpoint inhibitor-related pneumonitis (CIP) remains elusive. Here, we perform comprehensive single-cell analysis, specifically the combination of scRNA-seq and scTCR/BCR-seq, to profile molecular and cellular changes in CIP tissues and matched noncancerous adjacent tissues from lung cancer patients. CIP patients exhibit disrupted immune homeostasis, marked by expansion of the CD8⁺ tissue-resident memory T cell population, elevated IFNG expression and increased TCR clone sharing with other CD8⁺ T cells. We also identify increased IL-17A levels, robust IgG isotype class switching in B cells and GSDME-mediated macrophage pyroptosis as potential mechanisms involved in CIP. These findings provide valuable insights into the mechanisms underlying CIP and inform potential strategies for further intervention.