Liu et al. observed that the majority of T cells in high- and low-grade gliomas of 152 patients were in the perivascular cuffs. TIL/PBMC comparison showed elevated TIL expression of CXCR3, CCR5, CD25 and PD-1, and identified CD8+ and CD4+ TEFF TILs, pre-/exhausted CD8+ TILs, and a terminally differentiated, non-clonal IL-8+ CD4+ TIL population with innate-like features, which was associated with poor patient outcomes. In IL-8-humanized and cell transfer mouse models, IL-8-producing CD4+ T cells, myeloid cells, and tumor cells induced MDSC infiltration and angiogenesis, which promoted tumor growth and restricted ICB. Anti-PD-1 response was bolstered by interdiction of the IL-8/CXCR1/2 pathway.
Contributed by Paula Hochman
ABSTRACT: Malignant gliomas are largely refractory to immune checkpoint blockade (ICB) therapy. To explore the underlying immune regulators, we examine the microenvironment in glioma and find that tumor-infiltrating T cells are mainly confined to the perivascular cuffs and express high levels of CCR5, CXCR3, and programmed cell death protein 1 (PD-1). Combined analysis of T cell clustering with T cell receptor (TCR) clone expansion shows that potential tumor-killing T cells are mainly categorized into pre-exhausted/exhausted and effector CD8(+) T subsets, as well as cytotoxic CD4(+) T subsets. Notably, a distinct subpopulation of CD4(+) T cells exhibits innate-like features with preferential interleukin-8 (IL-8) expression. With IL-8-humanized mouse strain, we demonstrate that IL-8-producing CD4(+) T, myeloid, and tumor cells orchestrate myeloid-derived suppressor cell infiltration and angiogenesis, which results in enhanced tumor growth but reduced ICB efficacy. Antibody-mediated IL-8 blockade or the inhibition of its receptor, CXCR1/2, unleashes anti-PD-1-mediated antitumor immunity. Our findings thus highlight IL-8 as a combinational immunotherapy target for glioma.
Author Info: (1) Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing 400038, P.R. China; Jinfeng Laboratory, Chongqing 401329, P
Author Info: (1) Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing 400038, P.R. China; Jinfeng Laboratory, Chongqing 401329, P.R. China. (2) Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing 400038, P.R. China. (3) Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing 400038, P.R. China. (4) Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing 400038, P.R. China. (5) Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing 400038, P.R. China. (6) Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing 400038, P.R. China. (7) Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing 400038, P.R. China. (8) Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing 400038, P.R. China. (9) Department of Neurosurgery, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, P.R. China. (10) Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing 400038, P.R. China; Jiangsu Key Laboratory of Drug Screening, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, P.R. China. (11) Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing 400038, P.R. China; Jiangsu Key Laboratory of Drug Screening, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, P.R. China. (12) Genergy Biotechnology (Shanghai) Co., Ltd, Shanghai 200235, P.R. China. (13) Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing 400038, P.R. China. (14) Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing 400038, P.R. China. (15) Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing 400038, P.R. China. (16) Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing 400038, P.R. China. (17) Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing 400038, P.R. China. (18) Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing 400038, P.R. China. (19) Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing 400038, P.R. China. (20) Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing 400038, P.R. China. (21) Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing 400038, P.R. China. (22) Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing 400038, P.R. China. (23) Chongqing International Institute for Immunology, Chongqing 401338, P.R. China. (24) Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing 400038, P.R. China. (25) Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing 400038, P.R. China. (26) Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing 400038, P.R. China. (27) Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing 400038, P.R. China. (28) Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing 400038, P.R. China. (29) Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing 400038, P.R. China. (30) The Key Laboratory of the Digestive System Tumors of Gansu Province, Department of Tumor Center, Lanzhou University Second Hospital, Lanzhou 730030, P.R. China. (31) Jiangsu Key Laboratory of Drug Screening, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, P.R. China. (32) Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing 400038, P.R. China. (33) Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing 400038, P.R. China. (34) Institute of Cancer, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, P.R. China. (35) Medical Research Center, The Affiliated Changzhou No. 2 People's Hospital, Nanjing Medical University, Changzhou 213003, P.R. China. (36) Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing 400038, P.R. China. Electronic address: wang_yan1977@hotmail.com. (37) Department of Neurosurgery, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, P.R. China. Electronic address: lvsq0518@hotmail.com. (38) Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing 400038, P.R. China. Electronic address: bianxiuwu@263.net. (39) Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing 400038, P.R. China; Jinfeng Laboratory, Chongqing 401329, P.R. China. Electronic address: xindongliu@hotmail.com.
