Sarcoma Common MHC-I Haplotype Restricts Tumor-Specific CD8+ T Cell Response

Area of Science:

• Oncology
• Immunology
• Genetics

Background:

• Major histocompatibility complex (MHC) class I expression on cancer cells significantly influences T cell-mediated immunotherapy outcomes.
• Understanding Human Leukocyte Antigen (HLA) class I allelic variants and their expression is critical in rare sarcoma tissues, particularly in relation to PD-L1 status.

Purpose of the Study:

• To determine HLA class I allelic variants and expression levels in PD-L1-deficient and positive rare sarcoma tissues.
• To assess the impact of HLA class I down-regulation and deletion on T cell-mediated cytotoxicity in sarcoma patients.
• To propose a functional assay for evaluating individual patient tumor cell sensitivity to autologous T cell attack.

Main Methods:

• HLA class I (HLA-A, -B) and class II (HLA-DR-B) typing using genomic PCR.
• Analysis of HLA-A and -B mRNA and protein expression via quantitative PCR and immunohistochemistry.
• Functional cytotoxic assays involving co-culturing patient tumor biopsies with autologous T cells, with and without Nivolumab.

Main Results:

• The HLA-A24*:10-B73*:01 haplotype was identified as the most common.
• A significant down-regulation or deletion of HLA-B mRNA and HLA-A expression was observed compared to HLA-DR-B.
• HLA class I expression was often undetectable by immunohistochemistry; 32% of grade III cases were PD-L1 positive.
• Autologous T cell cytotoxic activity against matched tumor cells was restricted by HLA class I deletion/down-regulation, irrespective of PD-L1 status or Nivolumab treatment.

Conclusions:

• Down-regulation or deletion of HLA class I loci in individual sarcoma patients significantly limits autologous lymphocyte cytotoxic activity, impacting immunotherapy efficacy.
• The developed cytotoxic assay provides a patient-specific method to assess tumor cell susceptibility to T cell-mediated lysis, potentially guiding treatment strategies.