Associate Professor University of Louisville Louisville, Kentucky, United States
Disclosure(s):
Hui Zhang, PhD: No financial relationships to disclose
Introduction/Rationale: 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.
