Steatohepatitis alters lymphocytes cytotoxicity and localization, accelerating colorectal liver metastases

Abstract

Background & Aims

The liver is the most common site for distant metastasis. Metabolic dysfunction-associated fatty liver disease (MAFLD) is the most common liver disease worldwide and significantly increases the risk of liver metastasis in colorectal cancer (CRC) patients. We aimed to elucidate hepatic immune cells alterations in response to the metabolic stress in MAFLD and their influence on the early stages of CRC liver metastasis (CRLM).

Methods

High-fat diet (HFD) and Western diet (WD), were used to create MAFLD and MASH respectively. MC38 cancer cells were injected intrasplenically to create CRLM model. Single-cell RNA sequencing (scRNA-seq), RT-PCR and immunohistology were used to study hepatic immune-cell composition, phenotypes, and localization.

Results

Both diets significantly increased CRLM establishment, while only WD altered hepatic inflammation. The WD-promotes IL-10 and TGF-β1 elevation, an anti-inflammatory cytokines, inhibiting cytotoxic CD8⁺ T cells and NK cells and supporting an immunosuppressive environment. Although MASH led to an increased presence of hepatic CD8⁺ and NK cells, their infiltration into metastatic foci was reduced and was associated with a decrease in expression of cytotoxic markers. In our murine model of MASH, CD8⁺ T-cell depletion reduced the number of CRLM foci, which was accompanied by a decrease in IFN-γ-associated cytokines and a significant increase in the infiltration of granzyme-B expressing NK cells, ultimately enhancing cytotoxic killing ability.

Conclusions

This research underscores the crucial influence of diet-induced immune changes on CRLM establishment and progression. It illustrates that the co-localization of immune cells within liver metastases significantly affects their functionality, highlighting potential therapeutic strategies to balance immune exhaustion and activation.