Gemcitabine Modulates HLA-I Regulation to Improve Tumor Antigen Presentation by Pancreatic Cancer Cells

• Published in: International journal of molecular sciences 2024-03, Vol.25 (6), p.3211
• Main Authors: Larson, Alaina C, Knoche, Shelby M, Brumfield, Gabrielle L, Doty, Kenadie R, Gephart, Benjamin D, Moore-Saufley, Promise R, Solheim, Joyce C
• Format: Article
• Language: English
• Subjects: Antigen Presentation; Antigens, Neoplasm - therapeutic use; B cells; Cancer; Cancer cells; Cancer therapies; Cell Line, Tumor; Chemotherapy; Cytotoxicity; Deoxycytidine - therapeutic use; Drug approval; Gemcitabine; Histocompatibility antigens; Histocompatibility Antigens Class I - genetics; HLA histocompatibility antigens; human leukocyte antigen class I; Humans; immunomodulatory; immunoproteasome; Immunotherapy; Ligands; Lymphocytes; Mass spectrometry; Pancreatic cancer; Pancreatic Hormones; Pancreatic Neoplasms - metabolism; Patients; Peptides; Protein expression; Proteins; Retention; RNA; Scientific equipment and supplies industry
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms25063211

Pancreatic cancer is a lethal disease, harboring a five-year overall survival rate of only 13%. Current treatment approaches thus require modulation, with attention shifting towards liberating the stalled efficacy of immunotherapies. Select chemotherapy drugs which possess inherent immune-modifying behaviors could revitalize immune activity against pancreatic tumors and potentiate immunotherapeutic success. In this study, we characterized the influence of gemcitabine, a chemotherapy drug approved for the treatment of pancreatic cancer, on tumor antigen presentation by human leukocyte antigen class I (HLA-I). Gemcitabine increased pancreatic cancer cells' HLA-I mRNA transcripts, total protein, surface expression, and surface stability. Temperature-dependent assay results indicated that the increased HLA-I stability may be due to reduced binding of low affinity peptides. Mass spectrometry analysis confirmed changes in the HLA-I-presented peptide pool post-treatment, and computational predictions suggested improved affinity and immunogenicity of peptides displayed solely by gemcitabine-treated cells. Most of the gemcitabine-exclusive peptides were derived from unique source proteins, with a notable overrepresentation of translation-related proteins. Gemcitabine also increased expression of select immunoproteasome subunits, providing a plausible mechanism for its modulation of the HLA-I-bound peptidome. Our work supports continued investigation of immunotherapies, including peptide-based vaccines, to be used with gemcitabine as new combination treatment modalities for pancreatic cancer.