Another benefit of dietary fiber: The gut microbiome can modulate the immune system and influence the therapeutic response of cancer patients, yet the mechanisms underlying the effects of microbiota are presently unclear. Spencer et al . add to our understanding of how dietary habits affect microbiota and clinical outcomes to immunotherapy. In an observational study, the researchers found that melanoma patients reporting high fiber (prebiotic) consumption had a better response to checkpoint inhibitor immunotherapy compared with those patients reporting a low-fiber diet. The most marked benefit was observed for those patients reporting a combination of high fiber consumption and no use of over-the-counter probiotic supplements. These findings provide early insights as to how diet-related factors may influence the immune response. —PNK

Background: Type 1 conventional dendritic cells (cDC1s) possess efficient antigen presentation and cross-presentation activity, as well as potent T cell priming ability. Tissue-resident cDC1s (CD103⁺ cDC1s in mice, CD141⁺ cDC1s in humans) are linked with improved tumor control, yet the efficacy of immunotherapy using this population is understudied. Methods: We generated murine CD103⁺ cDC1s in vitro and examined their expression of cDC1-related factors, antigen cross-presentation activity, and accumulation in tumor-draining lymph nodes (TdLNs). The antitumor efficacy of the in vitro-generated CD103⁺ cDC1s was studied in murine melanoma and osteosarcoma models. We evaluated tumor responses on vaccination with CD103⁺ cDC1s, compared these to vaccination with monocyte-derived DCs (MoDCs), tested CD103⁺ cDC1 vaccination with checkpoint blockade, and examined the antimetastatic activity of CD103⁺ cDC1s. Results: In vitro-generated CD103⁺ cDC1s produced cDC1-associated factors such as interleukin-12p70 and CXCL10, and demonstrated antigen cross-presentation activity on stimulation with the toll-like receptor 3 agonist polyinosinic:polycytidylic acid (poly I:C). In vitro-generated CD103⁺ cDC1s also migrated to TdLNs following poly I:C treatment and intratumoral delivery. Vaccination with poly I:C-activated and tumor antigen-loaded CD103⁺ cDC1s enhanced tumor infiltration of tumor antigen-specific and interferon-γ⁺ CD8⁺ T cells, and suppressed melanoma and osteosarcoma growth. CD103⁺ cDC1s showed superior antitumor efficacy compared with MoDC vaccination, and led to complete regression of 100% of osteosarcoma tumors in combination with CTLA-4 antibody-mediated checkpoint blockade. In vitro-generated CD103⁺ cDC1s effectively protected mice from pulmonary melanoma and osteosarcoma metastases. Conclusions: Our data indicate an in vitro-generated CD103⁺ cDC1 vaccine elicits systemic and long-lasting tumor-specific T cell-mediated cytotoxicity, which restrains primary and metastatic tumor growth. The CD103⁺ cDC1 vaccine was superior to MoDCs and enhanced response to immune checkpoint blockade. These results indicate the potential for new immunotherapies based on use of cDC1s alone or in combination with checkpoint blockade.

Immune checkpoint blockade (ICB) has revolutionized cancer treatment, yet quality of life and continuation of therapy can be constrained by immune-related adverse events (irAEs). Limited understanding of irAE mechanisms hampers development of approaches to mitigate their damage. To address this, we examined whether mice gained sensitivity to anti-CTLA-4 (αCTLA-4)–mediated toxicity upon disruption of gut homeostatic immunity. We found αCTLA-4 drove increased inflammation and colonic tissue damage in mice with genetic predisposition to intestinal inflammation, acute gastrointestinal infection, transplantation with a dysbiotic fecal microbiome, or dextran sodium sulfate administration. We identified an immune signature of αCTLA-4–mediated irAEs, including colonic neutrophil accumulation and systemic interleukin-6 (IL-6) release. IL-6 blockade combined with antibiotic treatment reduced intestinal damage and improved αCTLA-4 therapeutic efficacy in inflammation-prone mice. Intestinal immune signatures were validated in biopsies from patients with ICB colitis. Our work provides new preclinical models of αCTLA-4 intestinal irAEs, mechanistic insights into irAE development, and potential approaches to enhance ICB efficacy while mitigating irAEs.

We previously reported that p15RS (p15INK4b Related Sequence), an RPR (Regulation of Nuclear Pre-mRNA) domain containing protein, inhibited Wnt signaling by interrupting the formation of the β-catenin/TCF4 complex. However, how p15RS functions as an intrinsic repressor to repress transcription remains unclear. In this study, we show that p15RS, through a specific interaction with HDAC2, a deacetylase that regulates gene transcription, maintains histone H3 in a deacetylated state in the promoter region of Wnt targeted genes where β-catenin/TCF4 is bound. We observed that HDAC inhibitors impair the ability of p15RS in inhibiting Wnt/β-catenin signaling. Depletion of HDAC2 markedly disabled p15RS inhibition of Wnt/β-catenin-mediated transcription. Interestingly, over-expression of p15RS decreases the level of acetylated histone H3 in the c-MYC promoter. Finally, we demonstrate that p15RS significantly enhances the association of HDAC2 (Histone Deacetylase 2) and TCF4, and enhances the occupancy of HDAC2 to DNA, resulting in the deacetylation of histone H3 and the failure of β-catenin interaction. We propose that p15RS acts as an intrinsic transcriptional repressor for Wnt/β-catenin mediated gene transcription at least partially through recruiting HDAC2 to occupy the promoter and maintaining deacetylated histone H3.