Project description:Cellular metabolic status profoundly influences T cell differentiation, persistence, and anti-tumor efficacy. By performing single-cell metabolic analyses of T cells from human cancer and mouse chronic infection atlases, we unveiled that diminished mannose metabolism is a prominent feature of T cell dysfunction. Conversely, experimental augmentation/restoration of mannose metabolism in adoptively transferred T cells via D-mannose supplementation enhanced anti-tumor activity and restricted exhaustion differentiation both in vitro and in vivo. Mechanistically, D-mannose treatment induced intracellular metabolic programming and increased the O-GlcNAcylation of β-catenin, which preserved Tcf7 expression and epigenetic stemness, thereby promoting stem- like programs in T cells. Finally, in vitro expansion with mannose supplementation yielded T cell products for adoptive therapy with stemness characteristics, even after extensive long-term expansion, that exhibited enhanced anti-tumor efficacy. Thus, these findings reveal cell-intrinsic mannose metabolism as a physiological regulator of CD8+ T cell fate, decoupling proliferation/expansion from differentiation, and underscored the therapeutic potential of mannose modulation in cancer immunotherapy.
Project description:Inactivation of tumor infiltrating lymphocytes (TILs) is one of the limiting factors of anti-tumor immunity during tumor onset and progression. Epigenetic abnormalities are regarded as a major culprit contributing to the dysfunction of TILs within tumor microenvironment. In this study, we used a murine model of melanoma to discover that Tet2 inactivation significantly enhances the anti-tumor activity of TILs, with the efficacy comparable to immune checkpoint inhibition imposed by anti-PD-L1 treatment. Single-cell RNA-seq analysis further reveals that Tet2-deficient TILs exhibit effector-like features. Transcriptomic and ATAC-seq analysis further demonstrated that Tet2 deletion reshapes the chromatin accessibility and favors the binding of transcription factors geared toward CD8+ T cell activation. In summary, our study establishes that Tet2 constitutes one of the epigenetic barriers contributing to dysfunction of TILs during anti-tumor immunity, and that Tet2 inactivation could benefit anti-tumor immunity and suppress tumor growth.
Project description:Mounting evidence has highlighted the importance of complement in the construction of an immunosuppressive tumor microenvironment (TME). Tumor cell-derived C3 has been previously reported, however, whether and how it acts on anti-tumor immunity remains to be elucidated. Here, we describe a unique role of tumor cell-derived C3 in suppressing anti-tumor immunity. Tumor cell-derived C3 was activated intracellularly, which results in generation of C3a. C3a could modulate tumor-associated macrophages (TAMs) via C3a-C3aR-PI3Kγ signaling, thereby repressing anti-tumor immunity. More importantly, deletion of C3 in tumor cells with high C3 expression is sufficient to enhance the efficacy of ɑPD-L1 treatment. Collectively, our present results suggest tumor cell-derived C3 may serve as a novel target in cancer immunotherapy, specifically targeting C3 in tumor cells to enhance anti-tumor immunity.
Project description:Chemotherapies have been shown to enhance anti-tumor immunity, but whether chemotherapies affect tumor-associated macrophages (TAMs) is still unclear. We found TAMs is different before and after chemotherapy by comparing proteomic profiles of TAMs before and after chemotherapy.
Project description:Chemotherapies have been shown to enhance anti-tumor immunity, but whether chemotherapies affect tumor-associated macrophages (TAMs) is still unclear. We found TAMs is different before and after chemotherapy by comparing proteomic profiles of TAMs before and after chemotherapy.
