Dynamic Gene Expression and Immune Cell Remodeling in DN T Cell-Mediated Antitumor Response to Breast Cancer 2257888
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. 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 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. 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. NIH/NCI grant R01CA276284 Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)