Combining IL-2-based immunotherapy with commensal probiotics produces enhanced antitumor immune response and tumor clearance

Abstract

BackgroundInterleukin-2 (IL-2) serves as a pioneer of immunotherapeutic agent in cancer treatment. However, there is a considerable proportion of patients who cannot benefit from this therapy due to the limited clinical responses and dose-limiting toxicities. Mounting evidence indicates that commensal microbiota shapes the outcome of cancer immunotherapies. In this study, we aim to investigate the enhancing effect of Akkermansia muciniphila (AKK), a beneficial commensal microbe receiving considerable attentions, on the antitumor efficacy of IL-2 and explore the underlying molecular mechanism.MethodsColorectal carcinoma patient-derived tumor tissues were used to evaluate the therapeutic efficacy of combination treatment. AKK was orally delivered to B16F10 and CT26 tumor-bearing mice along with systemic IL-2 treatment. Flow cytometry was carried out to analyze the tumor immune microenvironment. The molecular mechanism of the enhanced therapeutic efficacy was explored by RNA-seq and then verified in tumor-bearing mice.ResultsCombined treatment with IL-2 and AKK showed a stronger antitumor efficacy in colorectal cancer patient-derived tumor tissues. Meanwhile, the therapeutic outcome of IL-2 was significantly potentiated by oral administration of AKK in subcutaneous melanoma and colorectal tumor-bearing mice, resulting from the strengthened antitumor immune surveillance. Mechanistically, the antitumor immune response elicited by AKK was partially mediated by Amuc, derived from the outer membrane protein of AKK, through activating toll-like receptor 2 (TLR2) signaling pathway. Besides, oral supplementation with AKK protected gut barrier function and maintained mucosal homeostasis under systemic IL-2 treatment.ConclusionThese findings propose that IL-2 combined with AKK is a novel therapeutic strategy with prospecting application for cancer treatment in clinical practice.

Isolation of a Lactobacillus paracasei Strain with Probiotic Attributes from Kefir Grains

“…Concomitantly, topical injection of the extract managed to decrease tumor weight and volume in immunodeficient BALB/c mice injected with A375 cells [ 47 ]. Today, selected probiotics strains have been added to anticancer regimes with the aim to abrogate side effects of melanoma immunotherapy [ 48 ] or to enhance the success of therapy to non-responders [ 49 ]. However, this niche of probiotic research is at its infancy and further studies are required to determine the most effective strains, doses, and routes of administration.…”

Colorectal cancer and microbiota modulation for clinical use. A systematic review

“…The combination of A. muciniphila and IL-2 was significantly more effective than their separate actions in reducing tumor volume and increasing survival. 115 The effect of A. muciniphila appears to be related to a membrane protein called Amuc, which is recognized by Toll-like receptor 2 (TLR2). Cellular mechanisms and immune effects mediated by TLR2 lead to increased efficacy of IL-2 immune therapy.…”

“…Cellular mechanisms and immune effects mediated by TLR2 lead to increased efficacy of IL-2 immune therapy. 115…”

Clinical Application of Adaptive Immune Therapy in MSS Colorectal Cancer Patients

“…Regarding CRC, evidence has shown that IL-6 can activate autophagy through the IL-6/JAK2/BECN1 pathway and promote chemotherapy resistance in CRC ( 14 ). One recent study showed that combined treatment with IL-2 and Akkermansia muciniphila leads to stronger antitumor efficacy in CRC patient-derived tumor tissue and proposed this novel therapeutic strategy with prospecting application in the future ( 15 ). Another study showed that IL-2 combined with TNFSF14 results in an increase in CD8+ central memory cells and a decrease in tumor size in preclinical exploration ( 16 ).…”