ANXA10 sensitizes microsatellite instability-high colorectal cancer to anti-PD-1 immunotherapy via assembly of HLA-DR dimers by regulating CD74

Abstract

Background: Microsatellite instability-high (MSI-H) metastatic colorectal cancer (CRC) patients are the dominant population in immune checkpoint blockade treatments, while more than half of them could not benefit from single-agent immunotherapy. We tried to identify the biomarker of MSI-H CRC and explore its role and mechanism in anti-PD-1 treatments. Tumor-specific MHC-II was linked to a better response to anti-PD-1 in MSI-H CRC and CD74 promoted assembly and transport of HLA-DR dimers. Methods: The characteristic gene was screened by data analysis of single-cell and bulk transcriptome sequencing from public datasets. MSI-H CRC cells co-cultured with peripheral blood mononuclear cells and syngeneic model in C57BL/6 mice were performed to detect the sensitivity to anti-PD-1 treatments respectively. Results: ANXA10 was identified as a characteristic gene of MSI-H CRC and its expression was obviously greater in MSI-H than MSS CRC. ANXA10 significantly sensitized MSI-H CRC to anti-PD-1 treatments in vitro and in vivo. Specifically, ANXA10 promoted HLA-DR dimers in and on the surface of MSI-H CRC by increasing CD74 expression. Besides, this work demonstrated that ANXA10 contributed to better clinical benefits with anti-PD-1 therapy in MSI-H CRC patients. Conclusions: Our results provided a novel molecular marker ANXA10 to identify benefit population of MSI-H CRC for improving efficacy of anti-PD-1 and contributed to selection of treatment strategies.