Dr Gajewski on the Role of the Gut Microbiome in Immunotherapy Response Regulation

Thomas F. Gajewski, MD, PhD, AbbVie Foundation Professor of Pathology, professor of medicine, professor of Ben May Department of Cancer Research, University of Chicago Medicine, discusses the mechanism through which the gut microbiome modulates myeloid cells to regulate responses to immunotherapy, and how therapeutic approaches could potentially leverage this relationship.

Gajewski shares that prior research noted a correlation between the composition of the gut microbiome and outcomes with anti-PD1 therapy. In this preclinical study, certain bacterial entities were enriched in patients who had a response vs those who did not, Gajewski reports.

To investigate this mechanism further, researchers used reconstituted mice with patient-derived microbiota to model responders and non-responders to anti-PD1 therapy, Gajewski says. Through extensive immunological experiments and assays, including single-cell RNA sequencing (RNA-seq) of immune cells in the tumor microenvironment, Gajewski and colleagues observed that the primary shift in the tumor microenvironment was in the composition of myeloid cells, particularly macrophages and neutrophils. Favorable bacteria induced an inflammatory M1-like macrophage phenotype in the tumor, along with more inflammatory neutrophils, he says. Conversely, unfavorable microbiota from non-responders led to an M2-like macrophage phenotype, which is associated with immune regulation and tissue repair, along with granulocytes that resembled myeloid-derived suppressor cells, Gajeswki notes.

Clinical samples have shown that the M1/M2 balance correlates with anti-PD1 efficacy in patients, Gajewsk continues. Additionally, previously published microbiome intervention studies confirmed this correlation, showing that patients who responded to fecal microbiota transplantation followed by anti-PD1 therapy exhibited a shift towards an M1 macrophage phenotype when analyzing RNA-seq data from the tumor microenvironment, he details. This finding highlights the significant role of the gut microbiome in modulating immune responses and the efficacy of immunotherapy, emphasizing the potential for microbiome interventions to enhance treatment outcomes, Gajewski concludes.