‘Getting the T’ on T cell populations in colorectal cancer

Colorectal cancer can be treated using immunotherapy approaches that use the immune cells to target cancer cells and induce the killing of those cancer cells. Some colorectal cancer types have been more sensitive than others to immunotherapy. A few studies have shown that an increase in microsatellite instability (MSI)—the inability of DNA to repair mismatches that occur randomly following DNA replication in cells—can result in increased T cell infiltration and enhanced sensitivity to immunotherapy. Dr. Ulrike Peters (a Professor and Associate Director in the Public Health Sciences Division at Fred Hutchinson), Dr. Amanda Phipps (an Associate Professor also in the Public Health Sciences Division), and members of the Cancer Consortium wanted to better understand the landscape of T cells within colorectal tumor environments and compare these immune cell populations between tumors with high or low MSI. The team published their findings characterizing specific subpopulations of T cells in both MSI high and low colorectal cancer in the journal of Frontiers in Immunology. This work was also featured in a Cancer Discovery commentary including AACR NextGen Star award recipient Dr. Claire Thomas, the first author and postdoctoral research fellow in the Peters’ and Phipps’ lab.

MSI can result in cancer cells accumulating additional mutations and is generally considered a clinically relevant feature of tumors. It is thought that these additional mutations can result in abnormal proteins or neoantigens that attract T cells to the tumor. “This study helps us better understand how MSI status is related to different functioning T cell densities in colorectal tumors,” shared Dr. Thomas. To do this, the researchers used patient colorectal tumor biopsies and fluorescence labeling techniques to characterize T cell populations in tumor tissues. Several markers were used to differentiate T cell subtypes into naïve, memory and regulatory for CD4+ and CD8+ T cells. These immune cells have different roles for the immune response and offer different targets for immunotherapy. “Our study sheds light on how MSI status is associated with multiple different T cell subsets, such as helper and cytotoxic T cells, as well as naïve, memory, and regulatory subsets that each have different biological function,” shared Dr. Thomas. Knowing which T cell subset resides in the colorectal cancer tumor environment may provide some insight into the best method of targeting those cells to kill cancer cells using immunotherapy approaches.

Dr. Thomas shared her insight on their data, “One interesting finding from our study is that while tumors with low or no microsatellite instability (MSI-low/MSS) do have lower T cells for most subsets compared to MSI-high, those tumors still have reasonable numbers of T cells that could potentially be targeted for therapy. A recent meta-analysis (https://pubmed.ncbi.nlm.nih.gov/38734024/ ) found that tumors with high T cells regardless of MSI status both had comparable survival rates, suggesting that MSI-low/MSS tumors with high T cells could behave similarly to MSI-high tumors.” Bringing together their findings and this meta-analysis data, Dr. Thomas concluded that, “T cell densities may be useful in future research for identifying which patients may be good candidates for immunotherapy, as immunotherapies have been successful for the MSI-high subtype.” Therefore, in addition to knowing the type of T cells present in the tumor, knowing the abundance of these T cells may help predict the efficiency of immunotherapy-based approaches of treating colorectal cancer.

This research and related work aimed to better understand the immune populations of T cells in colorectal cancer in MSI high and low tumors. Funding for this work was in part supported by the R01 CA248857 and these projects utilized the Fred Hutchinson Cancer Center Clinical Research Support and Specialized Pathology Divisional Cores. These two core facilities along with the many other core support teams are available to all labs under the Cancer Consortium umbrella of the Fred Hutchinson Cancer Center, University of Washington, and Seattle Children’s.

The spotlighted research was funded by the National Institutes of Health, the National Health and Medical Research Council of Australia Investigator, University of Melbourne Dame Kate Campbell, Canada Institutes of Health Research, Canadian Cancer Society, Ontario Ministry of Research and Innovation, Prevent Cancer Foundation, Brigham and Women’s Hospital, Harvard T.H. Chan School of Public Health, Cancer Research UK Grand Challenge and American Cancer Society Clinical Research.

Fred Hutch/University of Washington/Seattle Children's Cancer Consortium members Drs. Li Hsu, Amanda Phipps and Ulrike Peters contributed to this work.

Thomas CE, Takashima Y, Wesselink E, Ugai T, Steinfelder RS, Buchanan DD, Qu C, Hsu L, Dias Costa A, Gallinger S, Grant RC, Huyghe JR, Thomas SS, Ogino S, Phipps AI, Nowak JA, Peters U. 2024. Association between somatic microsatellite instability, hypermutation status, and specific T cell subsets in colorectal cancer tumors. Front Immunol. 15:1505896.