Tumor-reactivity of d2 negative gdT cells and the role of the gdT cell receptor
abT cells engineered to express a defined gdTCR (TEG) to attack cancer cells have shown great promise when using a g9d2TCR to redirect abT cells. Reports by us and recent reports by others support the key role of the g9d2TCR in cancer recognition. We further emphasized the crucial role of the dTCR chain and that differences in CDR3 sequences of the dTCR chain modulates functional avidity of TEGs. We and others demonstrated that also d2 negative gdTCRs are able to redirect abT cells towards different tumor cell lines. However, some studies suggest that d2 negative gdTCRs play a minor role in the tumor recognition by d2 negative gdT cells. In addition for both modes of action for tumor-recognition, d2 negative gdTCR-dependent and -independent, it has been suggested that CMV infection is not only a major driver of d2 negative gdT cell expansion but also induces tumor-cross reactive d2 negative gdT cells. Therefore, we aimed to systematically explore frequencies of tumor reactive d2 negative gdT cells in naive repertoires (cord blood) and patients with or without CMV infection and examined the potential role the parental d2 negative gdTCR in anti-tumor reactivity of selected clones. We observed that approximately 30% of all tested clones were tumor-reactive, though no differences were observed between different sources. Surprisingly, none of the so far tested gdTCR did mediate strong anti-tumor reactivity of the parental clones. Though numbers of tested TCR sequences are still low, our data imply that tumor-reactivity of d2 negative gdT cells is frequently not mediated by the d2 negative gdTCR alone.