“What is the meaning of life” or “what is mission of life”, this question may be exploring forever for all the lives, including human, even bacterium, viruses etc. Fortunately, at least the survival or/and reproduction were found two major missions currently. Thus, the material resource become the most precious resource and the struggles also will be inevitable. The defense or immune defense become the most important and effective tool for all the lives to deal with these wars. Especially for human immune system, which possess the omnipotent antigen recognition receptor repertoire, and the best recognition system to distinguish “self” and “non-self”. Then the immune system must “keep the original intention and perform its mission” to fight against cancer cells.
Xiao-Dong Luo PhD, Professor
Zhi Dai PhD, Assistant Professor
Most cancer cells would escape the immune response or immune killing with multiple mechanisms, such as hiding the tumor-specific antigen (TSA), or absence of costimulatory activation ligands, even over-expression immune checkpoint ligands (PD-L1, ICOS-L, OX40L etc.). However, there still may be existed a small number of tumor cells that can normally present pMHC antigen signals and do not have any suppression signals of immune checkpoints for their high heterogeneity. Thus, these tumor cells could be used as antigen recognized signal by TCRs repertoire (1013-18 TCRs) to activate antigen-specific T-cell clones. Just like the famous immunologists Kohler G, Milstein C and their developed the hybridoma cell technology in 1974. They successfully picked out B-cell clone to generate monoclonal antibody for any antigens, because they fully understood recognized ability of immune system and applied the diversity of B-cell receptor libraries (>1011 BCRs). Then, how to recognize and pick out these tumor-specific T-cell clones are the most important and effective works for us.
Here, we supposed a model of T-cell activation independent of professional antigen presenting cell. Fortunately, we successfully demonstrated it, and found cell size or cell volume could be used to effectively distinguish and pick out these specific reactive T-cell clones. According to without use of both virus modification and professional APC, these tumor-specific killing T-cells could be generated fast and abundantly from peripheral blood within 5days. It might break a novel T-cells therapy field outside of CAR-T, TCR-T, TIL, LAK and CIK therapy. Moreover, the research might be attractive for more scientists of medicine, biology, structural biology, immunology, chemistry to improve the technics or to reveal the tumor-specific antigens and structure of specific binding TCR, even to explore less immunogenic and better penetrated natural molecules. Moreover, the target cells could be changed for any variant antigen cells, including tumor cells, senescent cells and infected cells etc.
Besides, according to it is natural recognition and lack of exogenous DNA/RNA modification, such as lentivirus, it will maximally avoid the non-specific reactive for TIL therapy and risk of secondary cancer for CAR-T therapy, which are the primary safe challenges for currently clinical treatment. Especially FDA announced that it begun to investigate the serious risk of secondary cancer following CAR-T treatment at November 28, 2023, and quickly labeled the Boxed Warning for all BCMA- and CD19-directed CAR-T cell therapy at January 24, 2024. Thus, the safety and specific reactive are the public’s important demands.
This work is the beginning and it only benefit for MHC+ tumors currently. How to deal with MHC- tumors and what is the clinical effect of this technology will need more scientists to join in future.