Beasley, G. M. | bioRxiv Science

bioRxiv2024

Inhibition of UBE2N in regulatory T-cells boosts immunity against cancer

Regulatory T (Treg) cells prevent autoimmunity and facilitate cancer immune evasion. Depletion of Tregs is a promising cancer therapy, but risks of autoimmune reactions hamper its clinical translation. Here, we demonstrate that temporally induced deletion of Ube2n in Tregs (Ube2nTreg-KO) of adult mice results in a robust expansion and activation of cytotoxic CD8+ T-cells in response to cancer cell challenges, producing a long-lasting survival benefit without autoimmune complications. The anti-tumor effect persists following adoptive T-cell transfer to T-cell-deficient Rag1-knockout mice. Single-cell transcriptomic analysis revealed that UBE2N deletion shifted immunosuppressive Tregs to effector-like T-cells. This shift is characterized by the downregulation of c-Myc target genes, resembling that observed in tumor-infiltrating Tregs of melanoma patients. Further analyses confirm that UBE2N maintains c-Myc protein stability via suppression of K48-Ubiquitin-mediated proteasomal degradation. Taken together, our studies uncover a hitherto unexplored and potentially druggable UBE2N/c-Myc signaling axis to eradicate Treg-enabled cancer immune escape.

cancer biology↗

bioRxiv2022

Intratumoral Recall of Childhood Vaccine-Specific CD4+ T cells Coordinates Type I and II Antitumor Immunity

BackgroundCD4+ T cells are key contributors to cancer immune surveillance. However, means to effectively harness CD4+ T cell help for cancer immunotherapy are lacking, and antitumor mechanisms of CD4+ T cells remain crudely defined. MethodsThe impact of polio immunization on polio virotherapy was tested in syngeneic murine melanoma and breast cancer models. Antitumor effects of polio and tetanus toxoid antigens were assessed in polio and tetanus immunized mice. T and B cell knockout mice, CD4+ T cell adoptive transfer, and eosinophil depletion demonstrated cell-type specific contributions to the antitumor efficacy of polio recall. Phenotyping of adoptively transferred OT-I (OVA-specific) T cells in B16-OVA tumor bearing mice, as well as adoptive transfer of T cells to naive tumor-bearing recipients, measured the impact of intratumor polio/tetanus recall on antitumor T cell immunity. Pan-cancer human transcriptome data sets were queried to test associations between eosinophils and Tregs; cytokine profiles of polio and tetanus recall were defined in human peripheral blood of healthy donors and cancer patients; CD40L blockade was used to determine dependency of recall antigen therapy on CD40:CD40L signaling. ResultsPrior vaccination against poliovirus substantially bolstered the antitumor efficacy of polio virotherapy in mice, and intratumor recall of poliovirus or tetanus immunity delayed tumor growth in a manner complemented by pattern recognition receptor agonist therapy and PD1 blockade. Intratumor recall antigens augmented antitumor T cell function, and caused marked tumor infiltration of type 2 innate lymphoid cells (ILC2s) and eosinophils, coinciding with decreased proportions of intratumor Tregs. Antitumor effects of recall antigens were mediated by CD4+ T cells, independent of CD40L signaling, and were dependent on both eosinophils and CD8+ T cells. Human PBMCs mounted diverse cytokine/chemokine responses, which were not impaired in patients with advanced cancer, and an inverse relationship between eosinophil and Treg signatures was observed across TCGA cancer types. ConclusionThis work defines cancer immunotherapy potential of childhood vaccines, reveals their utility to engage CD4+ T cell help for antitumor CD8+ T cells, and implicates eosinophils as antitumor effectors of CD4+ T cells.

immunology↗