Abstracts (complete list) - Wissenschaft Online

Matthias Eberl, David Vermijlen, Francesco Dieli, Nadia Caccamo, Serena Meraviglia,
Giuseppe Cicero, Andrew Roberts, Bernhard Moser, Hassan Jomaa, Adrian Hayday
The unexpected functional plasticity of human γδ T cells:
implications for immunotherapy and beyond
Human peripheral blood Vγ9/Vδ2 T cells expand extensively in many infections, in
reaction toward the microbial metabolite HMB-PP. This 'transitional' response of γδ T
cells, occurring temporally between the rapid innate and slower adaptive response, is
widely viewed as pro-inflammatory and/or cytolytic. However, under the influence of an
appropriate microenvironment, Vγ9/Vδ2 T cells readily assume features conventionally
associated with Th1 (IFN-γ, TNF-α), Th2 (IL-4, GATA3), and follicular B helper TFH cells
(CXCL13, IL-21R), respectively, as well as with professional antigen-presenting cells
(HLA-DR, CD86). Such broad plasticity emphasizes the capacity of human γδ T cells to
influence profoundly the nature of the immune response to different challenges, and is
of relevance for ongoing clinical applications. Among the molecular signatures identified,
tumour necrosis factor-related apoptosis-inducing ligand (TRAIL), for instance, was only
expressed by pro-inflammatory, Th1-like, but not by Th2-like or TFH-like Vγ9/Vδ2 T
cells. This could be directly corroborated in vivo in a phase I trial to promote non-MHCrestricted
anti-tumour efficacy in metastatic hormone-refractory prostate cancer, using
the Vγ9/Vδ2 T cell agonist zoledronate. Most patients treated with zoledronate in
combination with low-dose IL-2, but conversely only 2 out of 9 treated with zoledronate
alone, displayed a long-term shift of γδ T cells toward an activated effector/memory-like
state (TEM ), producing IFN-γ and perforin. These patients also maintained serum TRAIL
levels. Most importantly, γδ TEM cell numbers showed a correlation with declining
prostate-specific antigen levels and objective clinical outcomes. γδ T cell phenotypes and
serum TRAIL may thus constitute novel biomarkers of prognosis in metastatic cancer
immunotherapy. On a final note, our data also imply that while co-delivery of IL-2
appears crucial for optimal cytotoxicity, the considered use of other cytokines such as IL-
21 in carcinoma trials might potentially lead to an (unwanted or wanted) diversion of
the immune system away from a pro-inflammatory response.