Defining The Cooperation Between Mhc-I And Mhc-Ii Neoantigen-Driven T Cell Responses To Develop Effective Personalized Immunotherapies

Author

Charmelle Williams, The University of Texas MD Anderson Cancer CenterFollow

Author ORCID Identifier

0000-0001-8342-587X

Date of Graduation

8-2022

Document Type

Thesis (MS)

Program Affiliation

Biomedical Sciences

Degree Name

Masters of Science (MS)

Advisor/Committee Chair

Matthew Gubin, Ph. D.

Committee Member

Shabnam Shalapour, Ph.D.

Committee Member

Nils-Petter Rudqvist, Ph.D.

Committee Member

Stephanie Watowich, Ph.D.

Committee Member

Florencia McAllister, Ph.D.

Abstract

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 Braf^v600e 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 mLama4^I.mItgb1^II) was rendered sensitive to ICT. Preliminary data showed that α-CTLA-4-treated Y1.7 mLama4^I.mItgb1^II 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 mLama4^I.mItgb1^II 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.

Keywords

Immunology, Cancer, Immunotherapy, Neoantigen, Antigen-specific T cells, Tumor-specific antigen, Tumor-shared antigen, CD8 T cell, CD4 T cell, Melanoma