Overcoming Immune Evasion in CAR-T Therapies with Groundbreaking New Discoveries

Although our immune systems have the ability to fight cancer, tumors also have their own maneuvers to escape from immune attacks, such as restricting antigen recognition, inducing T cell exhaustion, or accumulating specific metabolites and signal factors within the tumor microenvironment, resulting in substantial difficulties in designing effective cancer therapies. 

In the latest study from the University of Pennsylvania School of Veterinary Medicine, researchers uncovered a detailed mechanism by which tumors could evade both the immune system and cancer therapies using genetically engineered CAR-T cells. The discovery published in the latest issue of the journal Cell Metabolism not only provides new insights for searching for new targets for anti-cancer therapies but also has the potential to improve CAR T performance by blocking cancer cells from using that mechanism.

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Uncovering Tumors’ Ability to Evade Immunity Through Trogocytosis

According to the research paper, the team led by Dr. Serge Y. Fuchs, Director of Mari Lowe Center for Comparative Oncology at the University of Pennsylvania (UPenn) School of Veterinary Medicine, revealed how tumor-derived factors (TDFs) stimulate a process called trogocytosis, by which cancer cells prompt T cells to ingest bits of the cancer cell membrane and evade immune detection as a result. 

Ideally, when T cells and cancer cells come into contact, cytotoxic T cells can recognize cancer cells as abnormal, surrounding them and performing the killing action. However, based on UPenn’s team findings, when cancer cells interact with T cells, in reality, they secrete TDFs, simulating trogocytosis in vitro. When this process occurs, T cells unwittingly “nibble” pieces of the cancer cell membrane. 

In the case that the membrane fragments involved include tumor-specific antigens, T cells may become much less active for unknown reasons. Moreover, these affected T cells may begin expressing tumor-specific antigens on their surfaces, making them appear to other T cells like cancer cells. As a result, their normal counterparts may kill them in a process called fratricide, causing a decline in killer T cell numbers and activity and allowing cancer cells to escape immune surveillance and grow further.

Linking TDFs and Trogocytosis

The team found that cytotoxic T cells exposed to TDFs experienced a marked suppression of the expression of the CH25H gene, which has been known for altering cells’ lipid membranes. This process would, in turn, cause depletion of 25-hydroxycholesterol (25HC), a cholesterol metabolite that could inhibit trogocytosis and prevent T cells from inactivating or undergoing fratricide, promoting the occurrence of trogocytosis. 

Another notable discovery made by the team was that TDFs could induce the ATF3 gene, encoding ATF3 protein, which suppressed the expression of the CH25H gene, stimulating trogocytosis in T cells. Overall, this ATF3-CH25H axis could reduce anti-tumor immunity, stimulate tumor growth, and impede the efficacy of CAR-T cell therapy. When they added back the metabolite produced by CH25H or eliminated ATF3, they could block trogocytosis and restore the ability of T cells to kill cancer cells.

The Hope for Improved CAR-T Cell Therapy

Based on the discovery that trogocytosis could impair the effectiveness of the engineered T cells delivered in CAR-T cell therapy, the researchers attempted an “armored CAR-T Cell” approach, modifying T cells to co-express the CH25H gene. This attempt succeeded as co-expression of CH25H boosted the efficacy of therapeutic CAR-T cells against tumors, improving the survival of mice with cancer compared to the unarmored CAR-T cells.

Dr. Fuchs believes that trogocytosis has much potential for exploration in terms of cancer immunity. His team will further investigate the roles of ATF3 and CH25H and other molecules involved in trogocytosis. He hopes these findings will be relevant in future clinical applications.

“I can see this going into use in CAR-T therapy quickly,” said Fuchs, “It’s ready to play.”

Author

Richard Chau