Journal
CANCER DISCOVERY
Volume 11, Issue 7, Pages 1844-1859Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2159-8290.CD-20-0987
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Funding
- Fondazione AIRC [21091]
- AIRC [21923]
- European Community's Horizon 2020 [635342-2 MoTriColor]
- CRUK
- FC AECC Accelerator Award [22795]
- Fondazione Piemontese per la Ricerca sul Cancro-ONLUS 5 per mille 2014
- Ministero della Salute [NET-2011-02352137]
- Fondazione Umberto Veronesi and FPRC 5 per mille 2017 Ministero Salute PTCRC-Intra 2020 (REGENERATION-YIG 2020 project)
- Stand Up To Cancer Colorectal Cancer Dream Team Translational Research grant [SU2C-AACR-DT22-17]
- Nuovo-Soldati Foundation
- Swim Across America Foundation Fellowship
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The inactivation of beta-2 microglobulin (B2M) does not reduce the efficacy of immune checkpoint inhibitors (ICPis) in MMRd tumors, and a unique role for CD4(+) T cells in tumor rejection is identified.
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 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.
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