TGF-beta 1 potentiates V gamma 9V delta 2 T cell adoptive immunotherapy of cancer

Despite its role in cancer surveillance, adoptive immunotherapy using gamma delta T cells has achieved limited efficacy. To enhance trafficking to bone marrow, circulating V gamma 9V delta 2 T cells are expanded in serum-free medium containing TGF-beta 1 and IL-2 (gamma delta[T2] cells) or medium containing IL-2 alone (gamma delta[2] cells, as the control). Unexpectedly, the yield and viability of gamma delta[T2] cells are also increased by TGF-beta 1 when compared to gamma delta(2] controls. gamma delta[T2] cells are less differentiated and yet display increased cytolytic activity, cytokine release, and antitumor activity in several leukemic and solid tumor models. Efficacy is further enhanced by cancer cell sensitization using aminobisphosphonates or Ara-C. A number of contributory effects of TGF-beta are described, including prostaglandin E2 receptor downmodulation, TGF-beta insensitivity, and upregulated integrin activity. Biological relevance is supported by the identification of a favorable gamma delta[T2] signature in acute myeloid leukemia (AML). Given their enhanced therapeutic activity and compatibility with allogeneic use, gamma delta[T2] cells warrant evaluation in cancer immunotherapy.