Resistance to checkpoint blockade therapy through inactivation of antigen presentation

By Moshe Sade-Feldman, Yunxin J. Jiao, Jonathan H. Chen, Michael S. Rooney, Michal Barzily-Rokni, J. Eliane, Stacey L. Bjorgaard, Marc R. Hammond, Hans Vitzthum, S. Blackmon and 21 more. Nature Communications, 2017

857 citations recorded by the source corpus.

Treatment with immune checkpoint blockade (CPB) therapies often leads to prolonged responses in patients with metastatic melanoma, but the common mechanisms of primary and acquired resistance to these agents remain incompletely characterized and have yet to be validated in large cohorts. By analyzing longitudinal tumor biopsies from 17 metastatic melanoma patients treated with CPB therapies, we observed point mutations, deletions or loss of heterozygosity (LOH) in beta-2-microglobulin (B2M), an essential component of MHC class I antigen presentation, in 29.4% of patients with progressing disease. In two independent cohorts of melanoma patients treated with anti-CTLA4 and anti-PD1, respectively, we find that B2M LOH is enriched threefold in non-responders (~30%) compared to responders (~10%) and associated with poorer overall survival. Loss of both copies of B2M is found only in non-responders. B2M loss is likely a common mechanism of resistance to therapies targeting CTLA4 or PD1. Resistance to immune-checkpoint blockade often occurs in treated patients. Here, the authors demonstrate that B2M loss is a mechanism of primary and acquired resistance to therapies targeting CTLA4 or PD-1 in melanoma patients.

Subfields: Immunology, Oncology

View Paper: https://www.semanticscholar.org/paper/f458ee72ae1ef07c19efd6db8522fa93420947da

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In Immunology

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Citations in the corpus

• Acquired Resistance to Immune Checkpoint Inhibitors (2020, background): “Sade-Feldman et al. profiled the transcriptomes of individual immune cells (48 samples from 32 patients with melanoma) receiving immunotherapy, enabling the detection of individual T cell populations and associated markers associated with ICI responders and non-responders (Sade-Feldman et al., 2018)”
• Identifying phenotype-associated subpopulations by integrating bulk and single-cell sequencing data (2021, positive): “Notably, B2M is a critical component of MHC class I antigen presentation and loss-of-function mutations in B2M have been reported in cancer patients resistant to immunotherapy 24 .”
• Cancer Immune Evasion Through Loss of MHC Class I Antigen Presentation (2021, background): “LOH and/or mutations in Jaks, and STATs are observed in cancers (143, 171).”
• Defining T cell states associated with response to checkpoint immunotherapy in melanoma (2018, neutral): “, 2014); defects in antigen presentation and IFNg pathways (Gao et al., 2016; McGranahan et al., 2017; Sade-Feldman et al., 2017; Zaretsky et al., 2016); and signatures of mesenchymal transition, wound healing, and angiogenesis (Hugo et al.”
• Integrative molecular and clinical modeling of clinical outcomes to PD-1 blockade in metastatic melanoma patients (2019, neutral): “To generate non-parametric geneset scores in individual samples, we generated single-sample GSEA (ssGSEA) projections 43 for genesets, using rank normalization, including the MHC-II HLA genes (HLA-DMA, HLA-DMB, HLA-DOA, HLA-DOB, HLA-DPA1, HLA-DPB1, HLA-DQA1, HLA-DQA2, HLA-DQB1, HLA-DQB2, HLA-DRA, HL”