CD4+ T-cell Immunity in the Peripheral Blood Correlates with Response to Anti-PD-1 Therapy

Cancer Immunology Research - Tập 8 Số 3 - Trang 334-344 - 2020
Hiroshi Kagamu1, Shigehisa Kitano1,2, Ou Yamaguchi1, Kenichi Yoshimura3, Katsuhisa Horimoto4, Masashi Kitazawa4, Kazuhiko Fukui4, Ayako Shiono1, Atsuhito Mouri1, Fuyumi Nishihara1, Yu Miura1, Kosuke Hashimoto1, Yoshitake Murayama1, Kyoichi Kaira1, Kunihiko Kobayashi1
11Division of Respiratory Medicine, Saitama Medical University International Medical Center, Hidaka, Saitama, Japan.
22Department of Experimental Therapeutics, National Cancer Center Hospital, Tokyo, Japan.
33Innovative Clinical Research Center, Kanazawa University, Kanazawa, Japan.
44Molecular Profiling Research Center for Drug Discovery, National Institute of Advanced Industrial Science and Technology, Koto-ku, Tokyo, Japan.

Tóm tắt

AbstractAccumulating evidence indicates that CD8+ T cells in the tumor microenvironment and systemic CD4+ T-cell immunity play an important role in mediating durable antitumor responses. We longitudinally examined T-cell immunity in the peripheral blood of patients with non–small lung cancer and found that responders had significantly (P < 0.0001) higher percentages of effector, CD62Llow CD4+ T cells prior to PD-1 blockade. Conversely, the percentage of CD25+FOXP3+ CD4+ T cells was significantly (P = 0.034) higher in nonresponders. We developed a formula, which demonstrated 85.7% sensitivity and 100% specificity, based on the percentages of CD62Llow CD4+ T cells and CD25+FOXP3+ cells to predict nonresponders. Mass cytometry analysis revealed that the CD62Llow CD4+ T-cell subset expressed T-bet+, CD27−, FOXP3−, and CXCR3+, indicative of a Th1 subpopulation. CD62Llow CD4+ T cells significantly correlated with effector CD8+ T cells (P = 0.0091) and with PD-1 expression on effector CD8+ T cells (P = 0.0015). Gene expression analysis revealed that CCL19, CLEC-2A, IFNA, IL7, TGFBR3, CXCR3, and HDAC9 were preferentially expressed in CD62Llow CD4+ T cells derived from responders. Notably, long-term responders, who had >500-day progression-free survival, showed significantly higher numbers of CD62Llow CD4+ T cells prior to PD-1 blockade therapy. Decreased CD62Llow CD4+ T-cell percentages after therapy resulted in acquired resistance, with long-term survivors maintaining high CD62Llow CD4+ T-cell percentages. These results pave the way for new treatment strategies for patients by monitoring CD4+ T-cell immune statuses in their peripheral blood.

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Cancer Immunology Research

Tập 8 Số 3

334-344

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