In a study published in Nature Immunology, Prof. LU Wei' group from the Shanghai Institute of Nutrition and Health of the Chinese Academy of Sciences, and the collaborators, revealed the in vivo relationship between T cell receptor (TCR) signaling intensity and the differentiation of T cell exhaustion in tumors, and suggested that regulating the TCR signaling intensity mediated by CARD11 can alter the clonal diversity of anti-tumor CD8 T cells in the tumor microenvironment and enhance the anti-tumor immune response.

CD8⁺ T cells in the tumor microenvironment undergo continuous stimulation by tumor antigens, leading to the differentiation of these cells into exhausted CD8⁺ T cells (Tex). Exhausted differentiation has long been considered a major factor that leads to tumor escape from immune surveillance. 

However, recent studies have shown that Tex still possesses some anti-tumor capabilities, but its functionality is constrained by the low antigenicity of tumors and multiple immunosuppressive receptors. Therefore, in-depth exploration of the molecular mechanisms behind Tex differentiation is of great significance for developing more effective tumor immunotherapy strategies.

In this study, the researchers utilized TCR signaling protein CARD11 mutants derived from immunodeficient patients to construct Card11 gene mutant mice, and they established tumor models based on various CARD11 mutant transgenic mice. They found that overly high CARD11 signaling intensity downstream of the TCR in CD8⁺ T cells blocked the differentiation of CD8⁺ T cells into an exhausted state in the tumor microenvironment. In contrast, a relatively moderate TCR signaling intensity promoted the accumulation of Tex differentiation within tumors.

Furthermore, the researchers sorted tumor-infiltrating CD8⁺ T cells for in vitro cytotoxicity experiments, and confirmed that Tex had a strong tumor cell-killing function. However, single-cell TCR sequencing of Tex revealed that such populations exhibited high oligoclonality with significantly limited diversity in their TCR repertoire, which means that Tex can only recognize a very limited range of tumor antigens. The continuous mutations and evolution of tumors led to antigen escape, ultimately preventing Tex from effectively eliminating tumors.

Moreover, the researchers elucidated how CARD11, as a scaffolding protein, regulates the intracellular transport and degradation of the TCR complex by sensing the intensity of upstream TCR signaling, thereby determining the differentiation fate of CD8 T cells. 

This study reveals a negative correlation between TCR signaling intensity and Tex differentiation, demonstrating that the limitation in tumor antigen recognition diversity may be a key reason why Tex is unable to eliminate tumors. It provides a new approach for cancer immunotherapy.