Dynamic Gene Expression and Immune Cell Remodeling in DN T Cell-Mediated Antitumor Response to Breast Cancer 2257888

Abstract

Abstract Introduction In the Ja281 KO mouse model, we found that transferring TCRαβ+CD4⁻CD8⁻ double-negative (DN) T cells into these mice inhibited breast cancer (BC) growth. This DN T cell transfer-mediated antitumor response depends on host NK cells and IFNγ, but is independent of IFNγ and perforin produced by the donor DN T cells. The underlying mechanism is unknown. Since implanted tumor cells fail to grow in the transferred mice, it is challenging to study the associated cellular and molecular processes. Methods Herein, we conducted a transcriptomic analysis to identify gene signatures related to cell signaling and functional changes. RNA sequencing was combined with antibody-mediated cell depletion to investigate the dynamic cellular and molecular changes. Results Results showed that 42 hours after tumor inoculation, the major biological processes and signaling pathways significantly upregulated in DN T-transferred mice compared to wild-type controls included glycolysis, fatty acid metabolism, enhanced NK cell activation and IFNγ production, and elevated CCL8 expression. By day 3 post-inoculation, IFNγ-induced signaling pathways were significantly elevated in the tumors of DN T-transferred mice. Additionally, myeloid cells were observed infiltrating the tumor site. On days 3 and 5 after tumor inoculation, genes related to antigen presentation, T cell differentiation and activation were consistently upregulated in tumors from DN T-transferred mice. Interestingly, antibody-mediated depletion of CD8+ but not CD4+ T cells partially restored BC growth in some the transferred Ja281 KO mice, although tumor development remained significantly delayed compared to non-transferred controls. Conclusion In summary, DN T cell transfer promotes glycolysis and fatty acid oxidation shortly after tumor inoculation, induces NK cell activation and type 1 myeloid cell infiltration within 2—3 days, and is followed by enhanced T cell activation. CD8+ T cells appear to play a role in the sustained control of BC growth in this model. Funding Source NIH/NCI grant R01CA276284 Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)