Circulation of gut-preactivated naïve CD8⁺T cells enhances antitumor immunity in B cell-defective mice

Abstract

The gut microbiome has garnered attention as an effective target to boost immunity and improve cancer immunotherapy. We found that B cell-defective (BCD) mice, such as µ-membrane targeted deletion (µMT) and activation-induced cytidine deaminase (AID) knockouts (KOs), have elevated antitumor immunity under specific pathogen-free but not germ-free conditions. Microbial dysbiosis in these BCD mice enriched the type I IFN (IFN) signature in mucosal CD8+ T cells, resulting in up-regulation of the type I IFN-inducible protein stem cell antigen-1 (Sca-1). Among CD8+ T cells, naïve cells predominantly circulate from the gut to the periphery, and those that had migrated from the mesenteric lymph nodes (mLNs) to the periphery had significantly higher expression of Sca-1. The gut-educated Sca-1+ naïve subset is endowed with enhanced mitochondrial activity and antitumor effector potential. The heterogeneity and functional versatility of the systemic naïve CD8+ T cell compartment was revealed by single-cell analysis and functional assays of CD8+ T cell subpopulations. These results indicate one of the potential mechanisms through which microbial dysbiosis regulates antitumor immunity.

B cell-derived GABA elicits IL-10+ macrophages to limit anti-tumour immunity

“…We next addressed the effect of GABA on cellular immune responses, using the MC38 colon carcinoma model in which B cells have been shown to inhibit anti-tumour T cell responses through antigen-non-specific mechanisms 8 , 9 . We confirmed that muMt –/– mice controlled tumour growth better than their WT counterparts (Fig.…”

The microbiome, gastrointestinal cancer, and immunotherapy

“…For instance, mice bearing MC38 tumors showed reduced CD8+ T‐cell proliferation and increased tumor growth when colonized with Helicobacter pylori following anti‐CTLA‐4, anti‐PD‐1, or oncolytic viral therapies 23 . In another study, MC38‐bearing B‐cell deficient mice had increased antitumor immunity via improved CD8+ INFγ+ T‐cell circulation due to microbial dysbiosis induced by their immune deficiency 24 . Antibiotic‐depleted MC38‐bearing mice have also been found to have reduced macrophages and dendritic cells and that Akkermansia supplementation rescues their response to anti‐PD‐1 therapy 25 .…”

Human Microbiota and Immunotherapy in Breast Cancer - A Review of Recent Developments

“…The relationship between the microbiota and CD8 T cells remains poorly characterized, although recent studies showed that microbiota-mediated activation of these cells has implications in immunity and the response to cancer therapies (Figure 1). Some bacterial metabolites, like lipopolysaccharide (LPS), activate innate immune response by TLR pathway stimulation and then boosted antitumour CD8 T cells that migrate from the gut to the periphery (11,15,16).…”