TGF-β1 potentiates Vγ9Vδ2 T cell adoptive immunotherapy of cancer
Richard Beatson, Ana C. Parente‐Pereira, Leena Halim, Domenico Cozzetto, Caroline Hull, Lynsey M. Whilding, Olivier Martínez, Chelsea Taylor, Jana Obajdin, Kim Ngan Luu Hoang, Benjamin Draper, Ayesha Iqbal, Tom Hardiman, Tomasz Zabinski, Francis Man, Rafael T. M. de Rosales, Jinger Xie, Fred Aswad, Daniela Achkova, Chung-Yang Ricardo Joseph, Sara Ciprut, Antonella Adami, Helge G. Roider, Holger Hess‐Stumpp, Balázs Győrffy, Jelmar Quist, Anita Grigoriadis, Anette Sommer, Andrew Tutt, David M. Davies, John Maher
Abstract
Despite its role in cancer surveillance, adoptive immunotherapy using γδ T cells has achieved limited efficacy. To enhance trafficking to bone marrow, circulating Vγ9Vδ2 T cells are expanded in serum-free medium containing TGF-β1 and IL-2 (γδ[T2] cells) or medium containing IL-2 alone (γδ[2] cells, as the control). Unexpectedly, the yield and viability of γδ[T2] cells are also increased by TGF-β1, when compared to γδ[2] controls. γδ[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-β are described, including prostaglandin E 2 receptor downmodulation, TGF-β insensitivity, and upregulated integrin activity. Biological relevance is supported by the identification of a favorable γδ[T2] signature in acute myeloid leukemia (AML). Given their enhanced therapeutic activity and compatibility with allogeneic use, γδ[T2] cells warrant evaluation in cancer immunotherapy.