T Cells in Colorectal Cancer: Unravelling the Function of Different T Cell Subsets in the Tumor Microenvironment

Abstract

Therapeutic options for metastatic colorectal cancer (mCRC) are very limited, and the prognosis using combination therapy with a chemotherapeutic drug and a targeted agent, e.g., epidermal growth factor receptor or tyrosine kinase, remains poor. Therefore, mCRC is associated with a poor median overall survival (mOS) of only 25–30 months. Current immunotherapies with checkpoint inhibitor blockade (ICB) have led to a substantial change in the treatment of several cancers, such as melanoma and non-small cell lung cancer. In CRC, ICB has only limited effects, except in patients with microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) tumors, which comprise about 15% of sporadic CRC patients and about 4% of patients with metastatic CRC. The vast majority of sporadic CRCs are microsatellite-stable (MSS) tumors with low levels of infiltrating immune cells, in which immunotherapy has no clinical benefit so far. Immunotherapy with checkpoint inhibitors requires the presence of infiltrating T cells into the tumor microenvironment (TME). This makes T cells the most important effector cells in the TME, as evidenced by the establishment of the immunoscore—a method to estimate the prognosis of CRC patients. The microenvironment of a tumor contains several types of T cells that are anti-tumorigenic, such as CD8+ T cells or pro-tumorigenic, such as regulatory T cells (Tregs) or T helper 17 (Th17) cells. However, even CD8+ T cells show marked heterogeneity, e.g., they can become exhausted, enter a state of hyporesponsiveness or become dysfunctional and express high levels of checkpoint molecules, the targets for ICB. To kill cancer cells, CD8+ T cells need the recognition of the MHC class I, which is often downregulated on colorectal cancer cells. In this case, a population of unconventional T cells with a γδ T cell receptor can overcome the limitations of the conventional CD8+ T cells with an αβT cell receptor. γδ T cells recognize antigens in an MHC-independent manner, thus acting as a bridge between innate and adaptive immunity. Here, we discuss the effects of different T cell subsets in colorectal cancer with a special emphasis on γδ T cells and the possibility of using them in CAR-T cell therapy. We explain T cell exclusion in microsatellite-stable colorectal cancer and the possibilities to overcome this exclusion to enable immunotherapy even in these “cold” tumors.

Relationship of FDG PET/CT imaging features with tumor immune microenvironment and prognosis in colorectal cancer: a retrospective study

“…Among the components of the tumor immune microenvironment, the degrees of CD4 + cell and CD163 + cell infiltration and IL-6 expression in cancer tissues were significantly correlated with FDG PET/CT imaging features of primary tumors. Although CD4 + T cells can polarize into different subsets, which either stimulate or inhibit the immune response to cancer cells, higher levels of CD4 + cell infiltration in tumor tissues were related to better clinical outcomes in colorectal cancer in previous studies [ 10 , 11 , 29 ]. In our study, MTV and TLG showed significant negative correlations with CD4 + cell infiltration and significant positive correlations with tumor grade.…”

“…M2 macrophages perform pro-tumoral functions by secreting diverse pro-inflammatory cytokines and enzymes, such as interleukin-6 (IL-6) and matrix metalloproteinase-11 (MMP-11) [ 8 , 9 ]. In contrast, CD4 + and CD8 + T cells play a crucial role in anti-tumor immunity and help change the tumor microenvironment into a more tumor-suppressive condition [ 10 , 11 ]. These diverse cells and components in the tumor immune microenvironment are considered potential treatment targets and prognostic factors for colorectal cancer [ 6 ].…”

Protocol for the collection and analysis of the different immune cell subsets in the murine intestinal lamina propria

“… 19 , 20 Dysregulated T cells have been implicated in several intestinal pathologies like colorectal cancer, inflammatory bowel disease and celiac disease. 21 , 22 , 23 Here, T cells isolated with the different digestion enzymes were analyzed using flow cytometry as shown in Figure 5 A. From the live CD45+ total leukocytes, TCR αβ and TCR γδ were used for gating αβ -T cells and γδ -T cells, respectively.…”