结直肠癌中的 T 细胞：揭示肿瘤微环境中不同 T 细胞亚群的功能

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 T cell receptor can overcome the limitations of the conventional CD8 + T cells with an T cell receptor. 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 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.