The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences Dissertations and Theses (Open Access)
DEFINING THE COOPERATION BETWEEN MHC-I AND MHC-II NEOANTIGEN-DRIVEN T CELL RESPONSES TO DEVELOP EFFECTIVE PERSONALIZED IMMUNOTHERAPIES
Author ORCID Identifier
Date of Graduation
Masters of Science (MS)
Matthew Gubin, Ph. D.
Shabnam Shalapour, Ph.D.
Nils-Petter Rudqvist, Ph.D.
Stephanie Watowich, Ph.D.
Florencia McAllister, Ph.D.
Immune checkpoint therapy (ICT) (e.g. anti-CTLA-4 (α-CTLA-4), anti-PD-1 (α-PD-1)) enables durable T cell-dependent anti-tumor immunity in certain cancer patients. Since a subset of patients respond to ICT, this work aims at developing a more in-depth understanding of T-cell responses to MHC class I (MHC-I) and MHC class II (MHC-II) tumor antigens that are derived from aberrant expression of non-mutant antigens or driver and passenger somatic alterations that can function as tumor neoantigens. We used a poorly immunogenic Brafv600e Pten-/- Cdkn2a-/- YUMM1.7 (Y1.7) murine melanoma line with a paucity of endogenous neoantigens that is unresponsive to ICT, and introduced model neoantigens previously identified in a murine sarcoma tumor line expressing the same MHC haplotype as the Y1.7 line. The MHC-I neoantigen used was formed by a G1254V point mutation in the Laminin alpha subunit-4 (Lama4) and the MHC-II neoantigen was formed by an N710T point mutation in Integrin beta-1 (Itgb1). Anti-CTLA-4-treated mice bearing the Parental Y1.7 melanoma displayed progressive tumor growth, whereas the modified Y1.7 line expressing mLama4 and mItgb1 (Y1.7 mLama4I.mItgb1II) was rendered sensitive to ICT. Preliminary data showed that α-CTLA-4-treated Y1.7 mLama4I.mItgb1II tumors reject in mice in a CD4+ T cell and CD8+ T cell-dependent manner. Additionally, intratumoral mLama4-specific CD8+ T cells were detected in α-CTLA-4-treated Y1.7 mLama4I.mItgb1II melanoma bearing mice. Overall this model will allow us to better understand T cell mediated anti-tumor responses to both MHC-I and MHC-II neoantigens, as well as shared, non-mutant melanoma antigens (e.g. Pmel/GP100 and Trp2), which may facilitate development of improved neoantigen-based personalized immunotherapies.
Immunology, Cancer, Immunotherapy, Neoantigen, Antigen-specific T cells, Tumor-specific antigen, Tumor-shared antigen, CD8 T cell, CD4 T cell, Melanoma
Allergy and Immunology Commons, Biological Phenomena, Cell Phenomena, and Immunity Commons, Medical Immunology Commons, Oncology Commons