cIAP1/2 antagonism eliminates MHC class I-negative tumors through T cell-dependent reprogramming of mononuclear phagocytes.

Autor: Roehle K; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.; Department of Immunology, Harvard Medical School, Boston, MA 02115, USA., Qiang L; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.; Department of Immunology, Harvard Medical School, Boston, MA 02115, USA., Ventre KS; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA., Heid D; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.; Department of Immunology, Harvard Medical School, Boston, MA 02115, USA., Ali LR; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.; Department of Immunology, Harvard Medical School, Boston, MA 02115, USA., Lenehan P; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.; Department of Immunology, Harvard Medical School, Boston, MA 02115, USA., Heckler M; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.; Department of Immunology, Harvard Medical School, Boston, MA 02115, USA., Crowley SJ; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA., Stump CT; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.; Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA., Ro G; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA., Godicelj A; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.; Department of Immunology, Harvard Medical School, Boston, MA 02115, USA., Bhuiyan AM; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.; Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA., Yang A; Division of Radiation and Genome Stability, Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA., Quiles Del Rey M; Division of Radiation and Genome Stability, Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA., Biary T; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.; Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA., Luoma AM; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.; Department of Immunology, Harvard Medical School, Boston, MA 02115, USA., Bruck PT; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA., Tegethoff JF; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA., Nopper SL; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA., Li J; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA., Byrne KT; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA., Pelletier M; Novartis Institute for Biomedical Research, Cambridge, MA 02139, USA., Wucherpfennig KW; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.; Department of Immunology, Harvard Medical School, Boston, MA 02115, USA., Stanger BZ; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA., Akin JJ; Novartis Institute for Biomedical Research, Cambridge, MA 02139, USA., Mancias JD; Division of Radiation and Genome Stability, Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA., Agudo J; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.; Department of Immunology, Harvard Medical School, Boston, MA 02115, USA., Dougan M; Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA., Dougan SK; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. stephanie_dougan@dfci.harvard.edu.; Department of Immunology, Harvard Medical School, Boston, MA 02115, USA.
Jazyk: angličtina
Zdroj: Science translational medicine [Sci Transl Med] 2021 May 19; Vol. 13 (594).
DOI: 10.1126/scitranslmed.abf5058
Abstrakt: Loss of major histocompatibility complex (MHC) class I and interferon-γ (IFN-γ) sensing are major causes of primary and acquired resistance to checkpoint blockade immunotherapy. Thus, additional treatment options are needed for tumors that lose expression of MHC class I. The cellular inhibitor of apoptosis proteins 1 and 2 (cIAP1/2) regulate classical and alternative nuclear factor κB (NF-κB) signaling. Induction of noncanonical NF-κB signaling with cIAP1/2 antagonists mimics costimulatory signaling, augmenting antitumor immunity. We show that induction of noncanonical NF-κB signaling induces T cell-dependent immune responses, even in β 2 -microglobulin (β 2 M)-deficient tumors, demonstrating that direct CD8 T cell recognition of tumor cell-expressed MHC class I is not required. Instead, T cell-produced lymphotoxin reprograms both mouse and human macrophages to be tumoricidal. In wild-type mice, but not mice incapable of antigen-specific T cell responses, cIAP1/2 antagonism reduces tumor burden by increasing phagocytosis of live tumor cells. Efficacy is augmented by combination with CD47 blockade. Thus, activation of noncanonical NF-κB stimulates a T cell-macrophage axis that curtails growth of tumors that are resistant to checkpoint blockade because of loss of MHC class I or IFN-γ sensing. These findings provide a potential mechanism for controlling checkpoint blockade refractory tumors.
(Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)
Databáze: MEDLINE
Externí odkaz: