title: A Threshold Level of Intratumor CD8+ T-cell PD1 Expression Dictates Therapeutic Response to Anti-PD1.
abstract: Despite successes, thus far, a significant proportion of the patients treated with anti-PD1 antibodies have failed to respond. We use mouse tumor models of anti-PD1 sensitivity and resistance and flow cytometry to assess tumor-infiltrating immune cells immediately after therapy. We demonstrate that the expression levels of T-cell PD1 (PD1(lo)), myeloid, and T-cell PDL1 (PDL1(hi)) in the tumor microenvironment inversely correlate and dictate the efficacy of anti-PD1 mAb and function of intratumor CD8(+) T cells. In sensitive tumors, we reveal a threshold for PD1 downregulation on tumor-infiltrating CD8(+) T cells below which the release of adaptive immune resistance is achieved. In contrast, PD1(hi) T cells in resistant tumors fail to be rescued by anti-PD1 therapy and remain dysfunctional unless intratumor PDL1(lo) immune cells are targeted. Intratumor Tregs are partly responsible for the development of anti-PD1-resistant tumors and PD1(hi) CD8(+) T cells. Our analyses provide a framework to interrogate intratumor CD8(+) T-cell PD1 and immune PDL1 levels and response in human cancer.
authors.affiliation: Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia. School of Medicine, University of Queensland, Herston, Queensland, Australia.
authors.forename: Shin Foong
authors.initials: SF
authors.lastname: Ngiow
authors.affiliation: Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia. School of Medicine, University of Queensland, Herston, Queensland, Australia.
authors.forename: Arabella
authors.initials: A
authors.lastname: Young
authors.affiliation: INSERM U1015, Villejuif, France. Institut de Cancérologie Gustave Roussy, Villejuif, France. Equipe labellisée Ligue contre le Cancer, University of Paris Sud XI, Villejuif, France. Center of Clinical Investigations in Biotherapies of Cancer (CICBT), Villejuif, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Jacquelot
authors.affiliation: INSERM U1015, Villejuif, France. Institut de Cancérologie Gustave Roussy, Villejuif, France. Equipe labellisée Ligue contre le Cancer, University of Paris Sud XI, Villejuif, France. Center of Clinical Investigations in Biotherapies of Cancer (CICBT), Villejuif, France.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Yamazaki
authors.affiliation: INSERM U1015, Villejuif, France. Institut de Cancérologie Gustave Roussy, Villejuif, France. Equipe labellisée Ligue contre le Cancer, University of Paris Sud XI, Villejuif, France. Center of Clinical Investigations in Biotherapies of Cancer (CICBT), Villejuif, France. Metabolomics and Cell Biology Platforms, Institut de Cancerologie Gustave Roussy, Villejuif, France.
authors.forename: David
authors.initials: D
authors.lastname: Enot
authors.affiliation: INSERM U1015, Villejuif, France. Institut de Cancérologie Gustave Roussy, Villejuif, France. Equipe labellisée Ligue contre le Cancer, University of Paris Sud XI, Villejuif, France. Center of Clinical Investigations in Biotherapies of Cancer (CICBT), Villejuif, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Zitvogel
authors.affiliation: Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia. School of Medicine, University of Queensland, Herston, Queensland, Australia. mark.smyth@qimrberghofer.edu.au.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Smyth
mesh_terms: D056704:Adaptive Immunity; D000230:Adenocarcinoma / Q000276:immunology / Q000628:therapy*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D060890:B7-H1 Antigen / Q000502:physiology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D003110:Colonic Neoplasms / Q000276:immunology / Q000628:therapy*; D015536:Down-Regulation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000276:immunology*; D007116:Immunization, Passive; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000378:metabolism*; D008325:Mammary Neoplasms, Experimental / Q000276:immunology / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000276:immunology / Q000378:metabolism; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D061026:Programmed Cell Death 1 Receptor / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D059016:Tumor Microenvironment / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D060890:B7-H1 Antigen; C498919:Cd274 protein, mouse; D009363:Neoplasm Proteins; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor