Spiking immunotherapy with a bacterial cocktail brings T cells back to the fight

Abstract

A recent study by Montalban-Arques et al.1 in Cell Host & Microbe shows that augmenting the function of the gut microbiota reduces tumor burden. Four Clostridiales species blocked tumor growth as efficient as chemotherapy or immunotherapy in colorectal cancer and melanoma.

Main text

Recent studies have highlighted the important role that gut microbiota play in both the prevention and treatment of several cancer types, including colorectal cancer (CRC). However, an outstanding need in the field of cancer treatment is improving response to immunotherapy, especially for metastatic CRC; ∼97% are refractory to immunotherapy because of being proficient for mismatch repair (pMMR) and microsatellite stable (MSI-L). Unfortunately, these tumors also have low immunogenicity; either the CD8+ T cells are activated but cannot enter the tumor environment or the tumor is in an “immune desert” and no longer recognized by the cytotoxic T cells. Thus, identifying a new approach that may augment standard chemo- or immunotherapy would be of great benefit in this population.

Montalban-Arques et al.1 in Cell Host & Microbe initially observed that azoxymethane and dextran sodium sulfate (AOM/DSS) induced significantly different tumor burdens in genetically identical (C57BL/6J) animals from separate vendors (Figure 1). Using 16S rRNA sequencing of gut microbiota, they identified a mixture of four Clostridiales species (CC4), Roseburia intestinalis, Eubacterium hallii, Faecalibacterium prausnitzii, and Anaerostipes caccae, based on the reduced presence of a marker of butyrate production, butyryl-CoA transferase. To provide clinical support for use of this mixture of Clostridiales species, Montalban-Arques et al.1 found that, from stool samples (285 CRC cases and 290 tumor-free controls), the order Clostridiales, namely R. intestinalis, E. hallii, and F. prausnitzii, was depleted in CRC, especially late stage. Furthermore, all four strains produce butyrate through different pathways,2 which led to the hypothesis that butyrate was a potentially protective mechanism; however, targeted butyrate pathway analysis showed no consistency with either CRC patients or healthy controls. Additionally, oral supplementation of the mice with sodium butyrate had no mitigating effect on the CRC tumors compared to placebo, thus diminishing the role of butyrate in the treatment effect mechanism.

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