Metabolic targeting of cancer associated fibroblasts overcomes T-cell exclusion and chemoresistance in soft-tissue sarcomas.
Publication Year:
2024
PubMed ID:
38509063
Funding Grants:
Public Summary:
Treatments that use T cells (a type of immune cell) to fight cancer can work well, but they often fail in tumors where immune cells can’t easily get inside. One reason for this is the tumor’s environment, which can block or limit immune cell access.
In this study, researchers looked at a type of cancer called soft-tissue sarcoma, which usually doesn’t respond well to T cell–based therapies. They focused on certain support cells in tumors called cancer-associated fibroblasts (CAFs), which help shape the tumor environment.
Using advanced techniques to study individual cells, they identified a specific group of CAFs, which they called “glycolytic CAFs” (or glyCAF). These cells use a high level of sugar metabolism and produce a signal (called CXCL16) that prevents cancer-fighting T cells from entering the tumor.
The researchers found that if they block this sugar metabolism, these barrier-forming cells decrease. As a result, more T cells can enter the tumor, and chemotherapy works better.
Overall, the study suggests that targeting these specific support cells—along with standard treatments—might improve how well therapies work for sarcoma and possibly other cancers. More research and clinical trials are still needed to confirm this approach in patients.
Scientific Abstract:
T cell-based immunotherapies have exhibited promising outcomes in tumor control; however, their efficacy is limited in immune-excluded tumors. Cancer-associated fibroblasts (CAFs) play a pivotal role in shaping the tumor microenvironment and modulating immune infiltration. Despite the identification of distinct CAF subtypes using single-cell RNA-sequencing (scRNA-seq), their functional impact on hindering T-cell infiltration remains unclear, particularly in soft-tissue sarcomas (STS) characterized by low response rates to T cell-based therapies. In this study, we characterize the STS microenvironment using murine models (in female mice) with distinct immune composition by scRNA-seq, and identify a subset of CAFs we termed glycolytic cancer-associated fibroblasts (glyCAF). GlyCAF rely on GLUT1-dependent expression of CXCL16 to impede cytotoxic T-cell infiltration into the tumor parenchyma. Targeting glycolysis decreases T-cell restrictive glyCAF accumulation at the tumor margin, thereby enhancing T-cell infiltration and augmenting the efficacy of chemotherapy. These findings highlight avenues for combinatorial therapeutic interventions in sarcomas and possibly other solid tumors. Further investigations and clinical trials are needed to validate these potential strategies and translate them into clinical practice.