The specific anti-cancer therapies developed by using the body’s own immune cells have now revolutionized. Such immunotherapeutics can provide patients with malignant hematological tumors or solid tumors with a durable anti-cancer response, but not every patient will respond. For many types of cancer, the presence of cytotoxic T cells (immune cells that kill cancer cells) in tumors is often directly related to the individual’s anti-cancer response and survival, but it cannot predict the anti-cancer efficacy. At present, it is not clear about what causes T cell to infiltrate the tumor. Researchers Jansen et al. published an article in the journal of Nature to reveal the unknown source of tumor-infiltrating T cells.
Because tumor cells continue to proliferate, tumor-targeting T cells must have similar capabilities to continue to grow and divide until the last remaining tumor cells are eliminated. In patients taking immunotherapy, the longer the life span of anti-tumor T cells, the better the patient’s treatment effect will be. Therefore, for effective immunotherapy, it is important to understand the factors that affect the sustained growth of T cells and tumor infiltration. Some clues about the existence of these factors already exist, such as the presence of telomere structures at the ends of chromosomes and the high-level expression of CD27 protein in T cells.
In addition to these factors, another clue comes from a subset of stem cell-like T cells called memory T cells. These cells can provide a long-lasting immune response and express high levels of TCF7 protein, which is essential for maintaining the stem cell-like state of T cells because they can express the CD8 protein (so the type of cells called CD8 T cells). Stem-cell-like cells can self-renew and produce many different types of T cells, including cytotoxic CD8 T cells. Previously, researchers found the presence of stem cell-like T cells in cancer patients. However, they did not know the anatomical location of these cells. Now, researchers Jansen et al. have discovered that human kidney tumors contain stem cell-like T cells, which are located in the tumor’s special niche.
The researchers revealed the mechanism of tumor-infiltrating cytotoxic CD8 T cell levels. They analyzed kidney tumor samples from patients undergoing tumor removal surgery and found that the level of T-cell infiltration varies greatly between different samples. Among cancer patients whose CD8 T cells accounted for less than 2.2% of the samples, the cancer would continue to grow, which indicates that surgery and the patient’s own immune response against the remaining cancer cells may not be sufficient to inhibit the progress of the disease. In contrast, when the infiltration rate is higher than 2.2%, the tumor growth rate is 4 times slower.
Researchers now find that stem cell-like T cells only exist at lower levels in tumors carrying lower levels of T cell infiltration, while tumors with higher levels of T cell infiltration contain higher levels of stem cell-like T cells. In order to obtain further results, the researchers analyzed the characteristics of gene expression in cells and the status of epigenetic modifications. They found that, compared to depleted cytotoxic CD8 T cells, stem cell-like T cells were able to express a unique immune signaling molecule called chemokines, which is directly related to better patient survival and high levels of key costimulatory molecules.
The epigenetic modification characteristics of T cells in tumors may be affected by factors in the tumor microenvironment, which will affect the ability of T cells to play the role of stem cells. At present, researchers do not know the effect of tumor microenvironment on cancer-targeted T cells, and they will study this in depth.
The expression of chemokines and chemokine binding receptors in stem cell-like T cells will be higher than normal levels, which is similar to cells in the lymphatic microenvironment. Lymphatic vessels are a special structure in which immune cells can move and support T cell activation and survival. Stem cell-like T cells are located in the special niche of tumors near the lymphatic vessels, which will drive T cells to target tumor tissues. Now researchers have revealed how functional stem-like T cells in tumors produce cytotoxic T cells.
The presence of stem cell-like T-cell is directly related to the longer progression-free survival in this study. In contrast, other common methods of assessing immune responses in tumors, such as the expression of the immune checkpoint protein PD-L1, may not reveal associations with progression-free survival in cancer patients.
At present, researchers Jansen and colleagues have revealed the molecular mechanisms by which stem cell niches are generated and maintained, and whether tumors can act on their own to escape the damaging effects of the immune system. The discovery that stem cell-like T cells exist in special niches in tumor suggests that the clinical use of such cells may increase the infiltration of immune cells and enhance the level of depleted T cells through immunotherapy, which will release T-cell responses to aid the success of anticancer treatment.