γ9 and δ2CDR3 domains regulate functional avidity of T cells harboring γ9δ2TCRs

Immunotherapy with innate immune cells has recently evoked broad interest as a novel treatment option for cancer patients. gamma 9 delta 2T cells in particular are emerging as an innate cell population with high frequency and strong antitumor reactivity, which makes them and their receptors promising candidates for immune interventions. However, clinical trials have so far reported only limited tumor control by adoptively transferred gamma 9 delta 2T cells. As a potential explanation for this lack of efficacy, we found unexpectedly high variability in tumor recognition within the physiologic human gamma 9 delta 2T-cell repertoire, which is substantially regulated by the CDR3 domains of individual gamma 9 delta 2TCRs. In the present study, we demonstrate that the reported molecular requirements of CDR3 domains to interact with target cells shape the physiologic gamma 9 delta 2T-cell repertoire and, most likely, limit the protective and therapeutic antitumor efficacy of gamma 9 delta 2T cells. Based on these findings, we propose combinatorial-gamma delta TCR-chain exchange as an efficient method for designing high-affinity gamma 9 delta 2TCRs that mediate improved antitumor responses when expressed in alpha beta T cells both in vitro and in vivo in a humanized mouse model. (Blood. 2012; 120(26): 5153-5162)