title: Agonistic CD40 mAb-Driven IL12 Reverses Resistance to Anti-PD1 in a T-cell-Rich Tumor.
abstract: The durability and efficacy of anti-human PD1 monoclonal antibodies (PD1 mAb) vary across different malignancies. Although an absence of tumor-infiltrating cytotoxic T lymphocytes has been identified as a cause for resistance to PD1 mAb, the presence of intratumor exhausted PD1hiT cells also contributes to insensitivity to this immune checkpoint therapy. In this study, we used mouse tumor models of PD1 mAb resistance that harbored PD1hiT cells and flow cytometry analysis of tumor-infiltrating leukocytes immediately post-therapy as a screening platform to identify agents that could resensitize T cells to PD1 blockade. We showed that an agonistic anti-CD40 mAb converted PD1hiT cells into PD1loT cells, reversing phenotypic T-cell exhaustion and allowing the anti-PD1 refractory tumors to respond to anti-PD1 therapy. PD1 downmodulation by anti-CD40 mAb relied upon IL12 but not IL23, CD80/CD86/CD28, or CD70/CD27. Consistent with a role for regulatory T cells (Treg) in promoting T-cell exhaustion, we also showed that intratumor Treg presented with a less activated and attenuated suppressive phenotype, marked by reductions in CTLA4 and PD1. Similar to anti-CD40 mAb, anti-CTLA4 mAb also lowered intratumor T-cell PD1 expression. Our study provides a proof-of-principle framework to systematically identify immune conditioning agents able to convert PD1hiT cells to PD1loT cells, with clinical implications in the management of anti-PD1 refractory patients. Cancer Res; 76(21); 6266-77. ©2016 AACR.
authors.affiliation: Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia. mark.smyth@qimrberghofer.edu.au shinfoong.ngiow@qimrberghofer.edu.au.|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: Cancer Immunoregulation and Immunotherapy Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Blake
authors.affiliation: Bone Marrow Transplant Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.|Department of Haematology and Bone Marrow Transplantation, Royal Brisbane and Women's Hospital, Butterfield St, Brisbane, Queensland, Australia.
authors.forename: Geoffrey R
authors.initials: GR
authors.lastname: Hill
authors.affiliation: Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: Hideo
authors.initials: H
authors.lastname: Yagita
authors.affiliation: School of Medicine, University of Queensland, Herston, Queensland, Australia.|Cancer Immunoregulation and Immunotherapy Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.
authors.forename: Michele W L
authors.initials: MW
authors.lastname: Teng
authors.affiliation: Bristol Myers Squibb Company, Redwood City, California.
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Korman
authors.affiliation: Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia. mark.smyth@qimrberghofer.edu.au shinfoong.ngiow@qimrberghofer.edu.au.|School of Medicine, University of Queensland, Herston, Queensland, Australia.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Smyth
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D019013:CD40 Antigens / Q000037:antagonists & inhibitors*; D018664:Interleukin-12 / Q000502:physiology*; D053759:Interleukin-23 / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000188:drug therapy* / Q000276:immunology; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors*; D013601:T-Lymphocytes / Q000502:physiology*; D050378:T-Lymphocytes, Regulatory / Q000502:physiology
chemical_list: D000911:Antibodies, Monoclonal; D019013:CD40 Antigens; D053759:Interleukin-23; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D018664:Interleukin-12