Abstract
Clinical outcomes in colorectal cancer (CRC) correlate with T cell infiltrates, but the specific contributions of heterogenous T cell types remain unclear. To investigate the diverse function of T cells in CRC, we profiled 37,931 T cells from tumors and adjacent normal colon of 16 patients with CRC with respect to transcriptome, TCR sequence, and cell surface markers. Our analysis identified phenotypically and functionally distinguishable effector T cell types. We employed single-cell gene signatures from these T cell subsets to query the TCGA database to assess their prognostic significance. We found 2 distinct cytotoxic T cell types. GZMK+KLRG1+ cytotoxic T cells were enriched in CRC patients with good outcomes. GNLY+CD103+ cytotoxic T cells with a dysfunctional phenotype were not associated with good outcomes, despite coexpression of CD39 and CD103, markers that denote tumor reactivity. We found 2 distinct Treg subtypes associated with opposite outcomes. While total Tregs were associated with good outcomes, CD38+ Tregs were associated with bad outcomes independently of stage and possessed a highly suppressive phenotype, suggesting that they inhibit antitumor immunity in CRC. These findings highlight the potential utility of these subpopulations in predicting outcomes and support the potential for novel therapies directed at CD38+ Tregs or CD8+CD103+ T cells.
Highlights
Colorectal cancer (CRC) is a highly prevalent cancer and a leading cause of cancer deaths worldwide [1]
(3, 4), the success of T-cell targeting immunotherapy in colorectal cancer (CRC) has been limited to a rare subset with high microsatellite instability (MSI-H tumors that only represent ~15% of CRC) that are characterized by higher degree of mutation due to defective DNA mismatch repair [5,6,7,8,9]
Prior studies performed through histology or bulk RNA-seq analysis demonstrated a relationship between T-cell infiltrates and clinical outcomes in CRC [2, 3, 9, 12, 57]
Summary
Colorectal cancer (CRC) is a highly prevalent cancer and a leading cause of cancer deaths worldwide [1]. Clinical outcomes in CRC are broken down by staging criteria which guide treatment and prognosis. These are imperfect criteria due to the large variability in survival outcomes, especially in stage II and III patients [2]. An improved molecular understanding of T cell infiltrates within cancers may enhance our ability to develop novel T cell-directed immunotherapies for treatment of CRC. Single-cell transcriptome analyses of T-cell infiltrates have been performed in several types of tumors including breast cancer (BRC), liver cancer, and CRC [7, 10,11,12,13]. The phenotype and function of T-cell subtypes in CRC as they relate to patient prognosis remain unclear.
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