Proportions of blood-borne Vδ1+ and Vδ2+ T-cells are associated with overall survival of melanoma patients treated with ipilimumab

Abstract

Human γδ T-cells possess regulatory and cytotoxic capabilities, and could potentially influence the efficacy of immunotherapies. We analyzed the frequencies of peripheral γδ T-cells, including their most prominent subsets (Vδ1+ and Vδ2+ cells) and differentiation-states in 109 melanoma patients and 109 healthy controls. We additionally analyzed the impact of γδ T-cells on overall survival (OS) calculated from the first dose of ipilimumab in melanoma patients. Higher median frequencies of Vδ1+ cells and lower median frequencies of Vδ2+ cells were identified in patients compared to healthy subjects (Vδ1+: 30% vs. 15%, Vδ2+: 39% vs. 64%; both p<0.001). Patients with higher frequencies of Vδ1+ cells (≥30%) had poorer OS (p=0.043) and a Vδ1+ differentiation-signature dominated by late-differentiated phenotypes. In contrast, higher frequencies of Vδ2+ cells (≥39%) were associated with longer survival (p=0.031) independent of the M category or lactate dehydrogenase (LDH) level. Patients with decreasing frequencies of Vδ2+ cells under ipilimumab treatment had worse OS and a lower rate of clinical benefit than patients without such decreases. Therefore, we suggest frequencies of both Vδ1+ and Vδ2+ cells as candidate biomarkers for outcome in melanoma patients following ipilimumab. Further studies are needed to validate these results and to clarify whether they represent prognostic associations or whether γδ T-cells are specifically and/or functionally linked to the mode of action of ipilimumab.

Insights into Local Tumor Microenvironment Immune Factors Associated with Regression of Cutaneous Melanoma Metastases by Mycobacterium bovis Bacille Calmette–Guérin

“…In summary, our study suggests an association of Vγ9Vδ2 T cells with IL-BCG-induced melanoma regressions, consistent with the latest clinical discovery that the frequency of Vδ2+ γδ T cells is positively correlated with overall survival in melanoma patients treated with ipilimumab (48). Analysis of gene expression profiles induces type 1 immunity and may promote a unique Vγ9Vδ2 T cell infiltration profile.…”

“…Meanwhile, very few CD3+ αβ T cells were activated and expanded from these PBMCs (Figure 3D). This rapid, preferential activation of Vγ9 γδ T cells is not only consistent with the role γδ T cells play in the early control of mycobacterial infections (9, 10) but also provides a mechanism by which Vγ9Vδ2 T cells could impact antitumor activity (38, 48). …”

“…Furthermore, γδ T cells are also present in regressed lesions that are not injected with BCG. This association suggests a primary role of γδ T cells in the induction of melanoma regressions (48). …”

“…Meanwhile, infection and stress also induce expression of the BTN3A family of molecules, putative molecules that present phosphoantigens to Vγ9Vδ2 T cells (22). It is not surprising, therefore, that IL-BCG treatment can induce melanoma regression at injected sites, and that these regressions are strongly associated with the presence of Vγ9Vδ2 T cells (48). Besides infection, tumors are stressed due to rapid growth, limited oxygen and nutrient supplies.…”

NK Cells and γδT Cells for Relapse Protection after Allogeneic Hematopoietic Cell Transplantation (HCT)

“…As NK cells[78] and also γδT cells[79] express checkpoint proteins, administration of checkpoint inhibitors is expected to increase NK and γδT cell responses. For example, blocking CTLA-4 in melanoma patients showed an association between tumor control and reconstitution of γ9δ2T cell repertoires [80]. …”