Immunotherapy treatment with anti-PD-1 and anti-CTLA4 has revolutionized the treatment of certain cancers, including melanoma. However, patients with colorectal cancer (CRC) are less responsive and only a small subset (<10%) benefit from treatment. This subset of patients include those that are deficient in DNA mismatch repair or have microsatellite instability (MSI). However, in CRC increases in tumor-infiltrating lymphocytes (TILs) are a better predictor of overall survival regardless of MSI status. There is limited understanding of the factors affecting TIL response quality in CRC patients and how this influences response to immunotherapy.
T cell factor 1 (TCF-1, encoded by the gene Tcf7) is a transcription factor important for T cell development and differentiation. In melanoma, TCF-1 marks a population of stem-cell like memory CD8+ T cells that are highly responsive to anti-PD1 treatment. However, the role of TCF-1 in T cell differentiation in the colon and in CRC is unknown. Measuring the quality of T cell responses in CRC patients will deliver new biomarkers to better predict overall survival, identify novel targets for new immunotherapies and better predict patient response to current immunotherapies.
We use Opal 7-plex fluorescent immunohistochemistry to identify various T-cell subsets and expression of TCF-1 in tissue microarray (TMA) and whole sections from stage III CRC. We show that TCF-1+ T-cells are found at different frequencies between patients and are located in the tumour stroma, but rarely among tumour cells. We identify both CD8+ and CD8- TCF-1+ T-cells. In some patients a population of TCF-1+γδ+CD8+ T cells is also present. We will correlate the presence of each T cell subset with patient survival, high risk pathological features, tumour genomic and molecular subtype. This work will improve our understanding of T cell differentiation in CRC and identify biomarkers for further investigation to predict patient survival and response to immunotherapy.