Cd4 t cell–dependent rejection of beta-2 microglobulin null mismatch repair–deficient tumors

Giovanni Germano, Steve Lu, Giuseppe Rospo, Simona Lamba, Benoit Rousseau, Sonia Fanelli, Denise Stenech, Dung T. Le, John Hays, Maria Grazia Totaro, Vito Amodio, Rosaria Chilà, Anna Mondino, Luis A. Diaz, Federica Di Nicolantonio, Alberto Bardelli

Research output: Contribution to journalArticlepeer-review

Abstract

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 immunocom-petent 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 intra-tumoral 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.

Original languageEnglish (US)
Pages (from-to)1844-1859
Number of pages16
JournalCancer discovery
Volume11
Issue number7
DOIs
StatePublished - Jul 2021

ASJC Scopus subject areas

  • Oncology

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