Tumor-reactivity of d2 negative gdT cells and the role of the gdT cell receptor

{beta}T cells engineered to express a defined {gamma}{delta}TCR (TEG) to attack cancer cells have shown great promise when using a {gamma}9{delta}2TCR to redirect {beta}T cells (1-9). Reports by us (1-9) and recent reports by others (10, 11) support the key role of the {gamma}9{delta}2TCR in cancer recognition. We further emphasized the crucial role of the {delta}TCR chain and that differences in CDR3 sequences of the {delta}TCR chain modulates functional avidity of TEGs (2, 8). We and others demonstrated that also {delta}2 negative {gamma}{delta}TCRs are able to redirect {beta}T cells towards different tumor cell lines (12-15). However, some studies suggest that {delta}2 negative {gamma}{delta}TCRs play a minor role in the tumor recognition by {delta}2 negative {gamma}{delta}T cells (16, 17). In addition for both modes of action for tumor-recognition, {delta}2 negative {gamma}{delta}TCR-dependent and -independent, it has been suggested that CMV infection is not only a major driver of {delta}2 negative {gamma}{delta}T cell expansion (18) but also induces tumor-cross reactive {delta}2 negative {gamma}{delta}T cells (19-21). Therefore, we aimed to systematically explore frequencies of tumor reactive {delta}2 negative {gamma}{delta}T cells in naive repertoires (cord blood) and patients with or without CMV infection and examined the potential role the parental {delta}2 negative {gamma}{delta}TCR 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 {gamma}{delta}TCR 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 {delta}2 negative {gamma}{delta}T cells is frequently not mediated by the {delta}2 negative {gamma}{delta}TCR alone.