Charité team finds reduced NKG2D on MAIT cells in 97 gastrointestinal cancer patients

A research team at Charité – Universitätsmedizin Berlin led by Katja Kotsch analyzed immune cells from 97 patients with five different gastrointestinal tumors. As reported by lomazoma.com, the study tracked mucosal-associated invariant T (MAIT) cells across blood, peritumoral tissue, and tumor tissue lomazoma.comlomazoma.comlomazoma.comOpen source ↗. The researchers found that tumor-infiltrating MAIT cells consistently downregulated the activating receptor NKG2D across all five cancer types. In hepatocellular carcinoma (HCC), this receptor loss directly correlated with patient survival rates and markers of liver damage.

Receptor downregulation and tumor infiltration

In patients with HCC and colorectal liver metastases, MAIT cells were enriched in peritumoral tissue compared to peripheral blood, but their numbers dropped significantly within the tumor mass itself. No significant density differences across tissue compartments emerged in colorectal, pancreatic, or gastric cancers. While the absolute frequency of circulating MAIT cells in blood remained comparable between cancer patients and healthy controls, NKG2D expression on circulating cells was markedly reduced in HCC and colorectal cancer. Following surgical tumor resection, patient monitoring for up to six months showed that circulating MAIT cell counts remained stable while surface NKG2D levels rose substantially, a rebound that also correlated with overall survival in HCC.

Disrupted activation pathways and cytotoxicity

Functional assays demonstrated that MAIT cells from peritumoral tissue generated higher levels of cytokines and defense molecules than those from blood, yet tumor-derived cells lost the capacity for polyfunctional cytokine production. Upon stimulation with interleukin-15 (IL-15), MAIT cells derived from blood and adjacent non-tumor liver tissue exhibited increased cytotoxicity against target cells, accompanied by upregulation of NKG2D and granzyme B. In contrast, MAIT cells isolated directly from HCC tumors failed to mount this cytotoxic response.

Investigation of the transcription factor XBP1s revealed that IL-15 activated this downstream pathway in circulating and peritumoral MAIT cells, whereas intratumoral HCC cells showed a severely blunted response lomazoma.comlomazoma.comlomazoma.comOpen source ↗. The findings indicate that the IL-15 and XBP1s signaling axis is impaired inside tumor microenvironments, positioning NKG2D as a candidate clinical marker for disease tracking.