1. Analysis of HLA gene expression in patients with dMMR/MSI-H colorectal carcinoma resistant to immune checkpoint inhibitors
- Author
-
Heinz-Josef Lenz, Theodore Nicolaides, Andrew Elliott, Richard M. Goldberg, John Marshall, Emil Lou, Anthony Frank Shields, Davendra Sohal, Benjamin Adam Weinberg, David Spetzler, Jim Abraham, Joanne Xiu, and Wolfgang Michael Korn
- Subjects
Cancer Research ,Oncology - Abstract
202 Background: Large studies have identified immune checkpoint inhibitors (ICI) as an effective therapy for deficient mismatch repair/microsatellite instability high (dMMR/MSI-H) colorectal cancer (CRC). However, a subset of dMMR/MSI-H CRC patients exist that do not benefit from ICI and show rapid cancer progression within the first 6 months of therapy. Genetic alterations of the host immune system, including loss of β2M and single copy loss of HLA molecules, can contribute to innate resistance to ICI. In this study, we sought to analyze the role of expression of HLA genes and β2M as determinants of innate resistance to ICI by analyzing an extensive clinico-genomic database. Methods: Next-generation sequencing (NGS) of DNA (592-gene or whole exome) and RNA (whole transcriptome) was performed on CRC patient samples (n = 24,394) submitted to a CLIA-certified laboratory (Caris Life Sciences, Phoenix, AZ). dMMR/MSI-H was assessed by IHC/NGS. PD-L1 expression was tested by IHC (SP142; positive (+): ≥2+, ≥%5). Real world overall survival and treatment data were obtained from insurance claims data. Time-To-Next-treatment (TTNT) was calculated from start of ICI monotherapy to the start of next therapy, or death. Kaplan-Meier estimates were used for comparison. A composite signature of MHC II gene expression was tested for molecular associations. Immune cell infiltration was estimated by RNA deconvolution using quanTIseq. Statistical significance was determined using Fisher’s Exact/Mann Whitney/X2 tests. Results: We identified 1549 patients with dMMR/MSI-H CRC; 242 patients of these had received pembrolizumab or nivolumab. Using TTNT as a proxy for progression on treatment, we divided the patients into two cohorts: >180 days TTNT and 180 days TTNT; good responders) and 34 patients (
- Published
- 2023
- Full Text
- View/download PDF