CD4 T Cell-Dependent Rejection of Beta-2 Microglobulin Null Mismatch Repair-Deficient Tumors.

Autor:	Germano G; Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Turin, Italy. alberto.bardelli@unito.it giovanni.germano@unito.it.; Department of Oncology, University of Torino, Candiolo, Turin, Italy., Lu S; Ludwig Center and Howard Hughes Medical Institute at Johns Hopkins, Baltimore, Maryland., Rospo G; Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Turin, Italy.; Department of Oncology, University of Torino, Candiolo, Turin, Italy., Lamba S; Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Turin, Italy., Rousseau B; Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York., Fanelli S; Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Turin, Italy.; Department of Oncology, University of Torino, Candiolo, Turin, Italy., Stenech D; Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Turin, Italy.; Department of Oncology, University of Torino, Candiolo, Turin, Italy., Le DT; Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland., Hays J; Division of Medical Oncology, Wexner Medical Center and James Cancer Hospital, The Ohio State University, Columbus, Ohio., Totaro MG; IFOM-the FIRC Institute of Molecular Oncology, Milan, Italy., Amodio V; Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Turin, Italy.; Department of Oncology, University of Torino, Candiolo, Turin, Italy., Chilà R; Department of Oncology, University of Torino, Candiolo, Turin, Italy.; IFOM-the FIRC Institute of Molecular Oncology, Milan, Italy., Mondino A; Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy., Diaz LA Jr; Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York., Di Nicolantonio F; Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Turin, Italy.; Department of Oncology, University of Torino, Candiolo, Turin, Italy., Bardelli A; Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Turin, Italy. alberto.bardelli@unito.it giovanni.germano@unito.it.; Department of Oncology, University of Torino, Candiolo, Turin, Italy.
Jazyk:	angličtina
Zdroj:	Cancer discovery [Cancer Discov] 2021 Jul; Vol. 11 (7), pp. 1844-1859. Date of Electronic Publication: 2021 Mar 02.
DOI:	10.1158/2159-8290.CD-20-0987
Abstrakt:	Inactivation of beta-2 microglobulin (B2M) is considered a determinant of resistance to immune checkpoint inhibitors (ICPi) in melanoma and lung cancers. In contrast, B2M loss does not appear to affect response to ICPis in mismatch repair-deficient (MMRd) colorectal tumors where biallelic inactivation of B2M is frequently observed. We inactivated B2m in multiple murine MMRd cancer models. Although MMRd cells would not readily grow in immunocompetent mice, MMRd B2m null cells were tumorigenic and regressed when treated with anti-PD-1 and anti-CTLA4. The efficacy of ICPis against MMRd B2m null tumors did not require CD8 + T cells but relied on the presence of CD4 + T cells. Human tumors expressing low levels of B2M display increased intratumoral CD4 + T cells. We conclude that B2M inactivation does not blunt the efficacy of ICPi in MMRd tumors, and we identify a unique role for CD4 + T cells in tumor rejection. SIGNIFICANCE: B2M alterations, which impair antigen presentation, occur frequently in microsatellite-unstable colorectal cancers. Although in melanoma and lung cancers B2M loss is a mechanism of resistance to immune checkpoint blockade, we show that MMRd tumors respond to ICPis through CD4 + T-cell activation. This article is highlighted in the In This Issue feature, p. 1601 . (©2021 American Association for Cancer Research.)
Databáze:	MEDLINE
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