Can germline variants contribute to the individuality of anti-tumor CD8 T cell response?

Uncovering the role of germline variants in anti-tumor CD8 T cell response

We present a straightfoward method which could be used to characterize patient-intrinsic variants that may potentially contribute to individuality of anti-tumor CD8 T cell response.

When it comes to fighting cancer, not all immune responses are created equal. While T cell receptor-induced signaling is known to play a significant role, the impact of human germline variants in shaping anti-tumor CD8 T cell response has been difficult to explore. 

T cells are an important component of the immune system that can recognize and kill cancer cells. However, the effectiveness of T cells can vary from person to person. One factor that can contribute to this variability is genetic variation in the germline, or inherited, DNA sequence. 

In this recent work, we developed a method to investigate the impact of germline genetic variants on the function of CD8 T cells, a type of T cell that plays a key role in fighting cancer. We focused on a type of genetic variant known as a phosphotyrosine-altering non-synonymous single nucleotide variation (pTyr-SNV), which can affect the membrane-proximal signaling events that regulate T cell activity. We developed a co-cultivation system using syngeneic mouse-derived metastatic cancer cell lines and TCR transgenic primary mouse CD8 T cells T cell to study the effect of human #pTyr-SNV variant on T cell signaling and cytotoxic activity against melanoma cells. 

Our results showed that the presence of single #pTyr-SNV variant enhanced the activity of T cells against melanoma cells. This study provides a new approach for investigating the impact of genetic variation on T cell activity and could help to uncover new genetic determinants of individual differences in anti-tumor immune response.

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• PMID: 36690075
 
• DOI: 10.1016/j.jgg.2023.01.001