Microbiota-controlled trafficking of immunosuppressive intestinal T cells into cancer

Introduction

Resistance of cancers to immune checkpoint blockade (ICB) can result from a deviated taxonomic composition of the intestinal microbiota. A surge in the Enterocloster genus, for instance following discontinuation of antibiotics or chronic inflammation caused by tumors, induces the downregulation of MAdCAM-1 in the ileal lamina propria and mesenteric lymph nodes through perturbations of biliary salts.

Mechanism of Action

In turn, the ileal MAdCAM-1 loss induces the exodus of immunosuppressive T lymphocytes expressing the MAdCAM-1 receptor α4β7, i.e., FoxP3+ RAR-related orphan receptor gamma t (RORγt+) regulatory (Tr17) cells, from the gut to distant tumors. Disruption of the MAdCAM-1–α4β7 axis compromises the efficacy of immunotherapy and reprograms the tumor microenvironment towards a regulatory phenotype.

Predictive Biomarker

Moreover, serum soluble MAdCAM-1 is a proxy of intestinal dysbiosis and a robust predictor of survival in cancer patients treated with ICB.

Research Objectives

To decipher the biological significance of these findings, we will first investigate the transcriptional and post-translational mechanisms regulating MAdCAM-1 expression and function (Task 1), in particular neuroendocrine and metabolic cues.

Task 1: Mechanisms of MAdCAM-1 Regulation

1. Investigate transcriptional mechanisms.
2. Examine post-translational mechanisms.
3. Focus on neuroendocrine and metabolic cues.

Next, a comprehensive phenotyping of the emigrating enterotropic T cells reaching the tumor by single cell transcriptomics and genomics, as well as specific genetic and immunopharmacological intervention on T lymphocytes and cancer cells, will lead to the identification of the molecular mechanisms regulating the gut-tumor axis (Task 2).

Task 2: Phenotyping Enterotropic T Cells

1. Conduct single cell transcriptomics and genomics.
2. Perform genetic and immunopharmacological interventions.
3. Identify molecular mechanisms regulating the gut-tumor axis.

We will investigate how enterotropic T cells homing to cancers maintain their proliferative and suppressive capacities, in particular in the light of the recognition of tumor and/or commensal antigens (Task 3).

Task 3: T Cell Functionality

1. Study the proliferative capacities of enterotropic T cells.
2. Assess the suppressive capacities of enterotropic T cells.
3. Explore recognition of tumor and/or commensal antigens.

Altogether, this approach will lay the molecular and metabolic foundations governing the MAdCAM-1–α4β7 gut immune checkpoint.