Scientists have identified stem cell-like T cells in tumors that may promote cytotoxic T cell recognition and destroy cancer cells

December 19, 2019 / BIOON/ --The specific anti-cancer therapy developed by using the immune cells of the body has now undergone revolutionary changes Such immunotherapy can make the patients with malignant stage blood cancer or solid tumor have a lasting anti-cancer response, but not everyone will have a response For many kinds of cancer, the cytotoxic T cells in the tumor (the immune cells that kill cancer cells The existence of cellular) is often directly related to the individual's anti-cancer response and survival, but it does not predict the patient's anti-cancer response At present, researchers don't know what is the cause of tumor infiltration of T cells in some patients Recently, researchers Jansen and others published an article in the journal Nature to reveal the unknown source of tumor infiltrating T cells Because tumor cells will continue to proliferate, tumor targeted T cells must have similar ability to continue to grow and divide until the last remaining tumor cells are eliminated In patients receiving immunotherapy, the longer the life span of anti-tumor T cells, the better the therapeutic effect of patients Therefore, for effective immunotherapy, understanding the impact on the sustained growth of T cells and The factors of tumor infiltration mechanism are very important Some clues about the existence of these factors have existed, such as the existence of telomere structure at the end of chromosome and the high level expression of CD27 protein in T cells Image source: Jansen et al, Nature 576465 – 470 (2019) doi: 10.1038/s41586-019-1836-5 in addition to these factors, another clue comes from stem cell like T cell subsets called memory T cells, which can provide long-term immune response and express high levels of tcf7 protein, which can maintain the stem cells of T cells Like state is crucial because it can express CD8 protein (hence this type of cell is called CD8 T cell); stem cell like cells can self renew and produce many different types of T cells, including cytotoxic CD8 T cells Previously, researchers found the existence of stem cell like T cells in the body of cancer patients However, they did not know the anatomical location of these cells Now researchers like Jansen and others found that human renal tumors contain stem cell like T cells, which are located in the special habitat of tumors The researchers revealed the mechanism of the change of T cell level of tumor infiltrating cytotoxic CD8 They analyzed the kidney tumor samples of patients undergoing tumor removal, and found that there would be a huge difference in T cell infiltrating level between different samples CD8 in sample In less than 2.2% of cancer patients with T cells, the researchers found that cancer in patients will continue to grow, which shows that the immune response of surgery and patients to resist residual cancer cells may not be enough to inhibit the progress of the disease In contrast, when the invasion rate threshold is higher than 2.2%, the cancer growth rate of patients will be four times slower Then the researcher Jansen et al Used flow cytometry to analyze the type and composition of T cells in tumor samples of patients, and identified two different groups of T cell types, one group including cytotoxic CD8 T cells, which can express high levels of anticancer molecules and immune checkpoint molecules, can drive cytotoxic T cells into a state of dysfunction called "depletion" When cancer cells are exposed to T cells for an extended period of time, T cell depletion will occur in the tumor microenvironment; another group of T cell types include stem cell like T cells Cells, which can produce cytotoxic CD8 T cells to help promote the body's effective anti-tumor immune response, now researchers have found that stem cell-like T cells only exist at a lower level in tumors with a lower level of T cell infiltration, while tumors with a higher level of T cell infiltration contain a higher level of stem cell-like t cells To get further results, the researchers analyzed the characteristics of gene expression and epigenetic modifications in cells, and found that compared with depleted cytotoxic CD8 In terms of T cells, stem cell-like T cells can express unique immune signal molecules called chemokines, which are directly related to patients' better survival rate and high level of key costimulatory molecules, which are necessary for T cells to differentiate into cytotoxic T cells Previous analysis of T cells revealed a progressive pattern of epigenetic modification, which resulted in stem cell-like T cells producing cytotoxic CD8 T cells and eventually depletion The epigenetic modification characteristics of T cells in tumors may be affected by factors in tumor microenvironment, which may affect the ability of T cells to play a role of stem cells For example, the concentration of potassium ion in tumors can regulate epigenetic modification, and then affect whether T cells in stem cell like state will produce cytotoxic CD8 T cells At present, researchers are not clear about tumors The effect of microenvironment on cancer targeted T cells will be further studied by later researchers The researchers pointed out that the expression of chemokines and chemokine binding receptors in stem cell-like T cells will be higher than normal, which is similar to the cells in the lymphatic microenvironment The lymphatic vessel is a special structure in which immune cells can move and support the activation and survival of T cells; stem cells Like T cells are located in the special habitat of tumors near the lymphatics, and they will be confined to the dense area of antigen-presenting cells, which will drive T cells to target tumor tissue Now researchers have revealed how stem cell like T cells in functional state in tumors produce cytotoxic T cells The researchers observed that the presence of protein markers in the stem cell-like T-cell habitat was directly related to the long progression free survival of participants in this study In contrast, other common methods for evaluating the immune response in tumors, such as the expression of immunocheckpoint protein PD-L1, may not reveal the association with progression free survival in cancer patients In previous studies, researchers have found that stem cell-like T cells express high levels of immune checkpoint molecules when they form depleted CD8 T cells In one example, blocking the immune checkpoint protein PD-1 may cause stem cell-like T cells to proliferate explosively, while these cells express tcf7 protein, similarly, in melanoma Patients with tcf7 and CD8 T cells will get better clinical prognosis if they receive immunotherapy of blocking immune checkpoint protein Relevant research results show that if patients' tumors contain stem cell like T cells, blocking immune checkpoint molecular therapy may benefit patients who receive surgical removal of tumors Now, researcher Jansen and his colleagues have revealed the molecular mechanism of the generation and maintenance of stem cell habitat, and whether tumors can play a role on their own to avoid the damage of the immune system; researchers have found stem cell like T cells in tumor specific habitat, and also shown that the clinical use of such cells may increase tumors The infiltration of immune cells in can also enhance the level of depleted T cells through immunotherapy, which will release the response of T cells to help successfully fight cancer Reference materials: [1] Jansen, C.S., prokhnevska, N., master, V.A et al An intra clinical maintenances and differentiates stem like CD8 T cells Nature 576465 – 470 (2019) doi: 10.1038/s41586-019-1836-5 [2] Suman Kumar vodnala & Nicholas P restifo Identifying the source of tumour infilling T cells, nature 576， 385-386 (2019) doi： 10.1038/d41586-019-03670-6