Spatial heterogeneity of tumor and CD8+ T cell metabolism in liver metastasis

Objective

While immune-based therapies targeting CD8+ T cells have transformed melanoma treatment, many patients still show inconsistent responses between primary tumors and metastases, particularly in the liver. CD8+ T cells face unique barriers in liver metastases, hindering their infiltration and suppressing their function. Recent studies show that CD8+ T cells adapt their metabolism based on the nutrients available in the tumor environment, and this metabolic adjustment plays a key role in their ability to fight cancer. Liver metastases have traditionally been studied as uniform in CD8+ T cell activity and metabolism; however, our findings reveal that each metastasis creates a distinct metabolic environment that impacts CD8+ T cell infiltration and function. This challenges the conventional view and highlights the hidden heterogeneity driving resistance to immunotherapy. Building on this, the SpaceMet project will address the three following key objectives. (1) Identify the functional mechanisms by which metabolite heterogeneity impacts CD8+ T cell infiltration and function. We will investigate the metabolic heterogeneity revealed through spatial metabolomics in mouse liver metastases using an in vitro assay that simulates CD8+ T cell infiltration and interaction with tumor cells under specific liver-like nutrient conditions. (2) Investigate to which extent the genetic background and cell of origin determine the formation and composition of heterogeneous metabolic environments in the liver. This will involve performing spatial metabolomics and immune profiling of liver metastases from melanoma with different genetic profiles, as well as from other cancers. (3) Advance metabolism-targeted immunotherapy for liver metastases towards preclinical applications. To achieve this, we will employ humanized mouse models and liver metastasis patient biopsies. We anticipate that understanding these local interactions will pave the way to overcome immune resistance in liver metastasis.