Characterizing the role of regulatory T (Treg) cells in the progression of aggressive mesenchymal-type colorectal cancer
Worldwide Cancer Research
University Medical Center Utrecht
Colorectal cancer (CRC) is one of the most common types of cancer in the Western world and the second most common cause of cancer-related mortality. Analysis of recurrent patterns of gene expression in CRC has led to the identification of four Consensus Molecular Subtypes (CMS1-4). Of all newly diagnosed CRC cases in the world (1.5 million worldwide), approximately 25% are CMS4 (375,000 new cases each year). CMS4, also known as the ‘mesenchymal subtype’, is characterized by high stromal content and high level TGFß signaling, an increased likelihood of distant metastases, and resistance to chemotherapy and EGFR-targeted therapy. Of all CRC-related deaths worldwide (700,000 per year) approximately 40% is estimated to be due to CMS4 (280,000). Arguably, the development of subtype-targeted therapy is most urgent for CMS4 CRC. We have recently found that CMS4 is characterized by a specific gene signature reflecting infiltration of regulatory T (TREG) cells and have found that mesenchymal-type CRC tumor organoids induce a dramatic increase in TREG cell numbers. This suggests that tumor cells may directly promote TREG cell expansion in CMS4, potentially contributing to local suppression of anti-tumor immunity. Here, a novel in vitro 3D CMS4 tumor organoid-TREG cell co-culture model will be used to determine the capacity of tumor cells to modulate TREG cell development, identity, expansion and phenotype. In parallel, novel in vivo mouse models for CMS4-like metastatic CRC will be utilized to further investigate TREG cell biology, and study the effect of TREG depletion on tumor growth and spontaneous metastasis formation. The enrichment of TREG cells in CMS4 CRC suggests that TREG -targeting therapy may be particularly effective against this subtype. However, more insight into TREG accumulation in CMS4 CRC, their function, and their role in metastasis and therapy resistance needs to be gained, before considering them as valid targets for therapy.
2.1 Biological and endogenous factors