Figure 3: Antigen-dependent and antigen-independent resistance.

Resistance to chimeric antigen receptor (CAR) T cell therapy can be categorized according to the context of antigen loss or retention. Antigen loss is most commonly due to mutations in the gene encoding the antigen itself. However, there have been cases of antigen loss due to accidental transduction of a tumour cell leading to ‘CAR masking’ of the tumour antigen, resulting in relapse. In addition, reduced levels of tumour antigen can result in relapse and may be owing to trogocytosis in which CAR molecules on T cells remove tumour antigen from the surface, internalize it, and begin expressing the tumour antigen themselves. Antigen-independent resistance is due to exhausted T cells. This can result from a suboptimal infusion product with a terminal effector phenotype, loss of death receptor signaling on tumour cells making them resistant to CAR T cell killing, and an immunosuppressive tumour microenvironment due to regulatory T (T_reg) cells and myeloid-derived suppressor cells (MDSCs) and their respective soluble factors. IL-10, interleukin-10; PGE₂, prostaglandin E₂; TGFβ, transforming growth factor β.

This figure is copyrighted by Nature Reviews Cancer and can be found at: https://www.nature.com/articles/s41568-020-00323-z.