Human Tumor-Infiltrating MAIT Cells Display Hallmarks of Bacterial Antigen Recognition in Colorectal Cancer

Abstract

Summary Growing evidence indicates a role for the gut microbiota in modulating anti-tumor treatment efficacy in human cancer. Here we study mucosa-associated invariant T (MAIT) cells to look for evidence of bacterial antigen recognition in human colon, lung, and kidney carcinomas. Using mass cytometry and single-cell mRNA sequencing, we identify a tumor-infiltrating MAIT cell subset expressing CD4 and Foxp3 and observe high expression of CD39 on MAIT cells from colorectal cancer (CRC) only, which we show in vitro to be expressed specifically after TCR stimulation. We further reveal that these cells are phenotypically and functionally exhausted. Sequencing data show high bacterial infiltration in CRC tumors and highlight an enriched species, Fusobacteria nucleatum, with capability to activate MAIT cells in a TCR-dependent way. Our results provide evidence of a MAIT cell response to microbial antigens in CRC and could pave the way for manipulating MAIT cells or the microbiome for cancer therapy.

Circulating CD8+ MAIT cells correlate with improved outcomes in anti-PD1 treated melanoma patients

“…2c and 2d). These results resonate with recent findings in colon cancer where MAIT cells, and in particular regulatory CD4 MAIT cells, were also found preferentially in the tumor tissue (Li et al, 2020).…”

“…Whether such tumor-derived compounds also contain potential MAIT antigens is currently unknown. A recent report from the Newell group showed that the frequency of MAIT cells co-expressing CD39 and PD1 correlates with intratumoral bacterial load in colon cancer (Li et al, 2020). While we observed higher frequencies in melanoma tumors from mucosal sites (nasopharynx and jejunum), CD4+, and to a lesser extent CD8+, CD39 + PD1 + MAIT cells were also observed in metastases to the adrenal gland and axillary lymph node, which are not normally associated with bacterial colonization (Fig.…”

“…However, an opposing result was found in patients diagnosed with esophageal cancer, multiple myeloma, or colorectal cancer, where higher levels of MAIT cells were associated with decreased disease burden and improved outcomes (Gherardin et al, 2018; Ling et al, 2016; Melo et al, 2019). Further confounding this topic, a recent study in colorectal cancer patients found that a regulatory subset of CD4+ MAIT cells is activated within the tumor microenvironment and the abundance of these cells is correlated with tumor bacterial load (Li et al, 2020). To date, the role of MAIT cells in responses to immune checkpoint inhibitors (ICIs) in human cancer patients is unknown.…”

An Unconventional View of T Cell Reconstitution After Allogeneic Hematopoietic Cell Transplantation

“…Interestingly, a recent study identified a new MAIT cell subset in human colorectal carcinomas. These cells were directly stimulated by intratumoral bacterial antigens via their TCR and exhibited a distinct exhaustion phenotype, which was not observed in the MAIT cells from adjacent tissue or peripheral blood mononuclear cells ( 68 ). Regarding hematologic malignancies, MAIT cells have only been studied in multiple myeloma, where they exhibited lower counts in the blood ( 56 , 69 ) and bone marrow ( 69 ) compared to healthy controls, and a higher expression of PD-1 ( 69 ).…”

New Insights Into the Cancer–Microbiome–Immune Axis: Decrypting a Decade of Discoveries

“…In CRC, increased infiltration of MAITs is observed, however, IFN- γ production is reduced ( 134 ), and this increased infiltration correlates with poor survival ( 135 ). Analyzing the MAITs from human CRC samples, Li et al were able to show that F. nucleatum in CRC tissue can specifically activate MAITs in a TCR-dependent fashion, leading to expression of CD39 ( 126 ). As MAITs can secrete cytotoxic cytokines and modulate anti-tumor immune ( 133 ), this study indicates that MAITs could emerge as another potential avenue for targeting the microbial-cancer crosstalk.…”