Regulatory T cells promote cancer by suppressing anti-tumor immune responses. We found that anti-LAP antibody which targets the latency-associated peptide (LAP)/TGF-β complex on Tregs and other cells enhances anti-tumor immune responses and reduces tumor growth in models of melanoma, colorectal carcinoma and glioblastoma. Anti-LAP decreases LAP+ Tregs, tolerogenic dendritic cells and TGF-β secretion, and is associated with CD8+ T cell activation. Anti-LAP increases infiltration of tumors by cytotoxic CD8+ T cells and reduces CD103+ CD8 T cells in dLNs and spleen. We identified a role for CD103+ CD8 T cells in cancer. Tumor-associated CD103+ CD8 T cells have a tolerogenic phenotype with increased expression of CTLA-4 and IL-10 and decreased expression of IFN-γ, TNF-α, and granzymes. Adoptive transfer of CD103+ CD8 T cells promotes tumor growth whereas CD103 blockade limits tumorigenesis. Thus, anti-LAP targets multiple immunoregulatory pathways and represents a potential approach for cancer immunotherapy.

γδ T cells have many known functions, including the regulation of antibody responses. However, how γδ T cells control humoral immunity remains elusive. Here we show that complete Freund’s adjuvant (CFA), but not alum, immunization induces a subpopulation of CXCR5-expressing γδ T cells in the draining lymph nodes. TCRγδ+CXCR5+ cells present antigens to, and induce CXCR5 on, CD4 T cells by releasing Wnt ligands to initiate the T follicular helper (Tfh) cell program. Accordingly, TCRδ−/− mice have impaired germinal center formation, inefficient Tfh cell differentiation, and reduced serum levels of chicken ovalbumin (OVA)-specific antibodies after CFA/OVA immunization. In a mouse model of lupus, TCRδ−/− mice develop milder glomerulonephritis, consistent with decreased serum levels of lupus-related autoantibodies, when compared with wild type mice. Thus, modulation of the γδ T cell-dependent humoral immune response may provide a novel therapy approach for the treatment of antibody-mediated autoimmunity.

Chronic inflammation can drive tumor development. Here, we have identified microRNA-146a (miR-146a) as a major negative regulator of colonic inflammation and associated tumorigenesis by modulating IL-17 responses. MiR-146a-deficient mice are susceptible to both colitis-associated and sporadic colorectal cancer (CRC), presenting with enhanced tumorigenic IL-17 signaling. Within myeloid cells, miR-146a targets RIPK2, a NOD2 signaling intermediate, to limit myeloid cell-derived IL-17-inducing cytokines and restrict colonic IL-17. Accordingly, myeloid-specific miR-146a deletion promotes CRC. Moreover, within intestinal epithelial cells (IECs), miR-146a targets TRAF6, an IL-17R signaling intermediate, to restrict IEC responsiveness to IL-17. MiR-146a within IECs further suppresses CRC by targeting PTGES2, a PGE2 synthesis enzyme. IEC-specific miR-146a deletion therefore promotes CRC. Importantly, preclinical administration of miR-146a mimic, or small molecule inhibition of the miR-146a targets, TRAF6 and RIPK2, ameliorates colonic inflammation and CRC. MiR-146a overexpression or miR-146a target inhibition represent therapeutic approaches that limit pathways converging on tumorigenic IL-17 signaling in CRC.