A47: Intratumoral Density of Regulatory T Cells Is a Predictor of Host Immune Response and Chemotherapy Response Rate in Metastases from Colorectal Cancer

Introduction: Regulatory T calls (Tregs) are a subset of CD4+ T lymphocytes known to dampen the host immune response against cancer cells. As a result, in most solid tumors a high density of Tregs is a poor prognosticator. In colorectal cancer (CRC), the role of Tregs is not as well defined. In this paper, we investigate the association between intratumoral Treg density and CRC tumor microenvironment and response to therapy.


Methods: xCell algorithm was used to estimate the intratumoral density of Tregs in a total of 911 CRC patients in the Cancer Genome Atlas (TCGA) and GCE39582 cohorts.


Results: We found that CRCs with a high density of Tregs enriched multiple pro-cancer signaling pathways compared to low-Treg CRCs, such as Epithelial Mesenchymal Transition, K-ras, Hypoxia, TGF-beta, TNF-alpha, and angiogenesis. Although high-Treg CRCs were not associated with mutation of K-ras, BRAF, TP53, nor neoantigens, it was associated with significantly high infiltration of CD8, CD4, M1 and M2 macrophage, and dendritic cells consistently in both TCGA and GSE39582 cohorts. In agreement, high-Treg CRCs enriched pro-immune/inflammatory gene signatures, such as inflammatory response, IFN-gamma and IFN-alpha response, IL2 and IL6 signaling, and allograft rejection gene sets. Interestingly, Treg infiltration was significantly higher in earlier stage CRC in TCGA. Importantly, we found that metastatic CRCs (but not primary tumors) with higher densities of Tregs were associated with a significantly higher response rate to mFOLFOX6 compared to low-Treg CRC metastases (88.9% response vs. 16.7%, p < 0.001). High-Treg CRC was also associated with better response to chemotherapy without bevacizumab, but not with. Additionally, high-Treg CRCs were associated with high expression of immune checkpoint molecules, including PD-L1/PD-L2, CTLA4, TIGIT, and BTLA, suggesting a possible susceptibility to immunotherapy.


Conclusions: Tregs in CRC are associated with multiple pro-cancer pathways, but also with immune cell infiltration and immune response, as well as response to chemotherapy, particularly in metastatic tumors.