Molecular mechanisms of solid cancer resistance to INFg/TNFa cytokines secreted by CAR-T cells

Collaborative Research Program 2024-2026

Immunotherapy has become part of many cancer treatment protocols. In addition to anti-immune checkpoint monoclonal antibodies (anti-PD1, anti-CTLA-4, etc.) and autologous T-cell therapy, CAR-T cell therapy is also receiving a lot of attention. The ability of CAR (chimeric antigen receptor)-T cells to kill foreign cells is mediated by their specific targeting of target cells provided by the CAR element. In addition, the domain organization of CAR not only allows T cells to specifically recognize the target antigen on the surface of a cancer cell, but also ensures signal transmission into the cell, thereby activating the cytotoxicity of T lymphocytes [1]. -2].
CAR-T therapy is extremely effective in the treatment of refractory/resistant hematological malignancies (up to 80% of responses), but the results of its use against solid tumors are not so impressive [3]. There are several reasons for this phenomenon: for example, the loss or mutation of a cancer antigen on the surface of a target cell disarms T cells, making them much less specific and able to kill cancer cells. Another important factor is the immunosuppressive effect of the tumor microenvironment (TMO) on T cells [4–6]. Finally, solid tumor cells can develop resistance to CAR-T treatment as they become tolerant to the cytokines IFNg and TNFa, which are secreted by cytotoxic lymphocytes upon its activation [7-9].
It is important to note that recent studies have shown that CAR-T cells, by releasing IFNg and TNFa, can kill neighboring tumor cells without synapse formation between each CAR and the corresponding cancer antigen [7] (Fig. 1). IFNg interacts with TNFα, promoting a special type of cell death known as PANoptosis [10, 11]. IFNg and TNFa induce PANoptosis by changing the ratio of Bcl2 and Bax proteins on the mitochondrial membrane, followed by release of cytochrome C and activation of caspase-9 and caspase-3 [12], i.e., cells die via the internal (mitochondrial) apoptosis pathway [12]. 13-16]. Mitochondrial-mediated cell death (MMCD) is known for its key role in the treatment of various cancers. MMCD can be triggered by a number of chemical compounds (for example, etoposide and cisplatin [17-18]), which either cause DNA damage in the nucleus and initiate p53-mediated expression of proapoptotic genes, or act directly on mitochondria, increasing cellular levels of ROS [16]. Thus, resistance to both chemotherapy and CAR-T may be due to the same universal mechanisms associated with mitochondrial apoptosis, despite the different nature of its induction.
Significance According to the oncological service of the Republic of Kazakhstan and the Ministry of Health, more than 13,000 people die from cancer every year in the country. Among them, colorectal cancer ranks third in terms of the number of deaths (9.3%). To reduce mortality from cancer, a comprehensive set of measures is needed, including the introduction of the most modern methods of therapy and our own developments in the field of modern technologies. Currently, more than 500 clinical trials of various cell products made using CAR-T technology, targeting more than 50 antigens in more than 20 types of tumors, are open worldwide. Basic research into the resistance of solid tumors to CAR-T therapy will help establish scientific directions in medical schools, help educate young professionals involved in CAR-T research and development, and lay the scientific foundation for the use of CAR-T in the clinic.