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Select intratumoral riboflavin-auxotrophic Enterococcus species enhance cell surface MR1 expression and MAIT TCR
Pakhi Birla1,2, Lansaol Yang1,2, Wanting Shan1,2
1Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD 21205.
Abstract:
Mucosal-associated invariant T (MAIT) cells are innate-like T cells capable of MR1-dependent immune surveillance, but how intratumoral bacteria modulate MR1 expression in human lung tumors remains unclear. We studied intratumoral MAIT cells from paired single-cell RNA and TCR sequencing datasets of tumor-infiltrating CD3 T cells isolated from non-small cell lung cancer tumors in patients receiving neoadjuvant PD-1 blockade therapy. MAIT cells were subclustered to identify conventional MAIT-associated TCR clonotypes, which were then used to examine how bacterial exposure impacts cell-surface MR1 expression and downstream MAIT TCR activation. We found that select intratumoral Enterococcus species (spp.) did not directly activate MAIT cells but enhanced MR1-dependent MAIT activation in the presence of exogenous 5-OP-RU by increasing cell-surface MR1 expression on antigen-presenting cells including dendritic cells, B cells, and mononuclear phagocytes. This increase in MR1 cell surface expression is modulated through a posttranscriptional mechanism consistent with altered intracellular processing and trafficking of MR1. These findings reveal a role for tumor-associated bacteria in modulating MR1-dependent innate-like T cell activation and provide a basis for future studies examining whether this process influences response to immune checkpoint blockade.
Insights
Intratumoral bacteria, specifically Enterococcus, enhance MR1 expression on antigen-presenting cells in lung tumors. This boosts MR1-dependent T cell activation, impacting immune surveillance and potential responses to cancer therapies.
Area of Science:
- Immunology
- Microbiology
- Oncology
Background:
- Mucosal-associated invariant T (MAIT) cells are crucial for MR1-dependent immune surveillance.
- The role of intratumoral bacteria in modulating MR1 expression in human lung tumors is not well understood.
Purpose of the Study:
- To investigate how intratumoral bacteria influence MR1 expression and MAIT cell activation in non-small cell lung cancer (NSCLC).
- To explore the impact of bacterial exposure on MR1-dependent T cell responses in the tumor microenvironment.
Main Methods:
- Analysis of single-cell RNA and TCR sequencing data from tumor-infiltrating T cells in NSCLC patients.
- Subclustering of MAIT cells to identify clonotypes and assess MR1 expression and MAIT TCR activation.
- Examination of the effects of specific intratumoral bacteria on MR1 cell-surface expression.
Main Results:
- Select intratumoral Enterococcus species enhanced MR1-dependent MAIT cell activation.
- Increased cell-surface MR1 expression was observed on antigen-presenting cells (dendritic cells, B cells, mononuclear phagocytes).
- This enhancement occurred in the presence of exogenous 5-OP-RU and was modulated by posttranscriptional mechanisms affecting MR1 processing and trafficking.
Conclusions:
- Tumor-associated bacteria play a role in modulating MR1-dependent innate-like T cell activation.
- Findings provide a basis for future research into bacterial influence on immune checkpoint blockade response in lung cancer.
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