Nature. A new idea to improve immunotherapy- MHC II tumor antigen regulates the body's anti-tumor immunity.

"Cancer immunoediting" refers to the dynamic process of interaction and game between the immune system and tumor cells, from monitoring, killing, balancing to escaping [1].immune checkpoint therapy (ICT) can target some immune checkpoint molecules, making the immune system continuously activated and killing tumor cells.for cancer patients with poor effect of other classical treatment methods, this therapy is worth trying [2-4].at present, both in basic research and clinical practice, it has been confirmed that MHC I (major histocompatibility complex class I) tumor antigen can be targeted by CD8 + cytotoxic T lymphocytes (CTLs), so as to effectively kill [5-9] and recognize MHC Do CD4 + T cells of type II tumor antigen play a role in tumor immunity? Recently, Robert D. Schreiber's team from Washington University in St. Louis published an online article entitled MHC-II neoantigens shape tumour immunity and response to immunity in the journal Nature. It was found that effective anti-tumor response requires not only CD8 + T cells to recognize tumor antigens, but also CD4 + T cells.in addition, CD4 + T cells that recognize MHC type II tumor antigen are activated only in the tumor microenvironment.these results suggest that MHC type II tumor antigen is an important part of tumor immunity.first of all, the authors developed a new tumor antigen prediction algorithm hmmhc (a hidden Markov Model-based MHC binding predictor), and screened and predicted that the n710y mutant of mitgb1 (integrin - β 1) might be the MHC type II tumor antigen of T3 sarcoma cells.next, the author confirmed this conjecture by ELISPOT and other methods.next, the author began to study whether CD4 + T cells, which can recognize MHC type II tumor antigen, participate in tumor immunity.kp9025 sarcoma cell model (KP) was adopted by the authors. This cell has three characteristics: first, it is non immunogenic, that is, it does not produce immune response, which shows that anti-PD-1 + anti-CTLA4 immunocheckpoint therapy (ICT) does not work, the second is oncogene driven, and the third is that the tumor antigen does not mutate.the authors expressed MHC-I (mlama4) and MHC-II (mitgb1) tumor antigens in these cells, and then injected these cells into the subcutaneous of mice to establish the sarcoma model.the results showed that the KP expressing mlama4 or mitgb1 alone still had no effect, while the KP expressing mlama4 and mitgb1, that is, KP expressing MHC type I and II tumor antigens, could be recognized and killed by the immune system, and ICT played a role.these results suggest that both immune response and ICT require both CD8 + T cells activated by MHC type I tumor antigen and CD4 + T cells activated by MHC type II tumor antigen.in order to further study the role of CD4 + T cells in tumor immunity, the authors used the in vivo T cell cytotoxicity assay [10] to study the killing efficiency of CD8 + T cells under different conditions by detecting the proportion of specific labeled cells.the authors found that KP and KP.mLAMA4 In tumor mice, CD8 + T cells were not cytotoxic KP.mLAMA4 The mice with mitgb1 tumor had good killing effect on the cells containing MHC type I antigen.these results suggest that CD4 + T cells can mediate the cytotoxic effect of activated CD8 + T cells.finally, the authors studied the area of action of CD4 + T cells. the authors used the bilateral tumor experiment, i.e., injected on the same mouse side KP.mLAMA4 . mitgb1 was injected on the other side KP.mLAMA4 And ICT was carried out, KP.mLAMA4 . mitgb1 tumor cells did not grow, and KP.mLAMA4 Growth is normal, but relatively slow. these results suggest that CD4 + T cells only function in the lesion, but not in the other side of the tumor. to sum up, the authors found that CD4 + T cells activated by MHC type II tumor antigen can activate CD8 + killer T cells in the tumor microenvironment, so that the immune system can continue to activate and kill tumor. there are two highlights in this article. First, it proposes the new function of CD4 + T cells in tumor immunity. Previously, scholars have paid more attention to CD8 + killer T cells, because this cell type can directly kill tumor cells. However, the mechanism of their development, maturation, activation and inhibition is not fully understood. This article gives a mechanism of its continuous activation Through CD4 + T cells. the second is to put forward a new idea to improve immunotherapy. The killing effect of CD8 + T cells is often limited, and the immunocheckpoint therapy of anti-PD-1 + anti-CTLA4 often fails to achieve the expected effect of killing tumor, that is to say, the so-called "drug resistance" is produced The activation of CD4 + T cells by class II antigen can overcome this problem, which is the hope of cancer treatment. Schreiber, R. D., old, L. J. & amp; Smyth, M. J. cancer immunoediting: integrating immunity's roles in cancer suppression and promotion. Science 331, 1565 – 1570 (2011). 2. Larkin, J. et al. 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