ICOS+CD4+ T cells define a high susceptibility to anti–PD-1 therapy–induced lung pathogenesis
Mari Yokoi, Kosaku Murakami, Tomonori Yaguchi, Kenji Chamoto, Hiroaki Ozasa, Hironori Yoshida, Mirei Shirakashi, Katsuhiro Ito, Yoshihiro Komohara, Yukio Fujiwara, Hiromu Yano, Tatsuya Ogimoto, Daiki Hira, Tomohiro Terada, Toyohiro Hirai, Hirotake Tsukamoto
Mari Yokoi, Kosaku Murakami, Tomonori Yaguchi, Kenji Chamoto, Hiroaki Ozasa, Hironori Yoshida, Mirei Shirakashi, Katsuhiro Ito, Yoshihiro Komohara, Yukio Fujiwara, Hiromu Yano, Tatsuya Ogimoto, Daiki Hira, Tomohiro Terada, Toyohiro Hirai, Hirotake Tsukamoto
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Research Article Aging Immunology

ICOS+CD4+ T cells define a high susceptibility to anti–PD-1 therapy–induced lung pathogenesis

Abstract

Managing immune-related adverse events (irAEs) caused by cancer immunotherapy is essential for developing effective and safer therapies. However, cellular mechanism(s) underlying organ toxicity during anti–PD-(L)1 therapy remain unclear. Here, we investigated the effect of chronological aging on anti–PD-(L)1 therapy–induced irAE-like lung toxicity, utilizing tumor-bearing aged mice. Anti–PD-(L)1 therapy facilitated ectopic infiltration of T and B cells, and antibody deposition in lungs of aged but not young mice. Adoptive transfer of aged lung–derived CD4+ T cells into TCR-deficient mice revealed that both pathogenic CD4+ T cells and an aged host environment were necessary for the irAE-inducible responses. Single-cell transcriptomics of lung-infiltrating cells in aged mice demonstrated that anti–PD-(L)1 therapy elicited ICOS+CD4+ T cell activation. Disruption of the ICOS-ICOSL interaction attenuated germinal center B cell differentiation and subsequent lung damage, which were overcome by local administration of IL-21 in the lungs of anti–PD-1 therapy–treated aged mice. Therefore, ICOS+CD4+ T cells elicited under an aged environment exacerbated aberrant immune responses and the subsequent lung dysfunction. Consistent with the findings from the mouse model, ICOS upregulation in CD4+ T cells was associated with later irAE incidence in patients with cancer. These finding will help development of useful strategies for irAE management in patients with cancer, many of whom are elderly.

Authors

Mari Yokoi, Kosaku Murakami, Tomonori Yaguchi, Kenji Chamoto, Hiroaki Ozasa, Hironori Yoshida, Mirei Shirakashi, Katsuhiro Ito, Yoshihiro Komohara, Yukio Fujiwara, Hiromu Yano, Tatsuya Ogimoto, Daiki Hira, Tomohiro Terada, Toyohiro Hirai, Hirotake Tsukamoto

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Figure 3

ICOS-expressing effector CD4+ T cells excessively accumulate in lung tissues of aged mice.

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ICOS-expressing effector CD4+ T cells excessively accumulate in lung tis...
MC38-bearing young or aged mice were treated with anti–PD-L1 Ab. (A–C) Lung-infiltrating CD45+ cells were isolated from MC38-bearing young or aged mice that were treated with anti–PD-L1 Ab, and then were analyzed by scRNA-seq. Cluster analysis was performed and plotted by UMAP dimensionality reduction. Subclustering was performed on the data from the Cd4+ T cell populations in young and aged mice, and lower bar plots in A indicate their frequencies. Dot plots shown in B represent the expression of canonical marker genes across the indicated Cd4+ subclusters. Relative expression of indicated genes across subclustered populations from young and aged mice are shown in C. (D) Representative images of DAPI staining (left) and in situ RNA hybridization (right; white, ICOS; red, CD19; green, CD4) in lung from aged mice are shown. Scale bars: 100 μm (left) and 50 μm (right). (E) Representative dot plots of CD45 iv- cell populations within the lungs are shown. (F) Frequencies of indicated lung-infiltrating CD45– cell populations were assessed in mice treated with indicated Abs. Data are represented as mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001 by 1-way ANOVA followed by Tukey-Kramer post hoc test.