TGF-β1 potentiates Vγ9Vδ2 T cell adoptive immunotherapy of cancer

Abstract

Summary 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.

Generation and application of TGFβ-educated human Vγ9Vδ2 T cells

“…If cells are expanded in the same way but using IL-2 alone, they are referred to as γδ[2] cells. Note: Our RNA sequencing data suggests that cells are not phenotypically mature at day 8 ( Beatson et al., 2021 ). We therefore recommend completing the 15 day culture period.…”

“…Note: Our RNA sequencing data suggests that cells are not phenotypically mature at day 8 ( Beatson et al., 2021 ). We therefore recommend completing the 15 day culture period.…”

“…We also describe in vivo testing of the antitumor activity of these CAR T cells in mice. For complete details on the use and execution of this protocol, please refer to Beatson et al. (2021) .…”

“…For complete details on the use and execution of this protocol, please refer to Beatson et al. (2021) .…”

Cancer-Homing CAR-T Cells and Endogenous Immune Population Dynamics

“…A key player in immunosuppression is TGF-β, and TGF-β-counteracting therapies have shown favorable impact in distinct settings [ 79 ]. However, TGF-β1 operates as an activation signal for Vγ9Vδ2 T cells in the adoptive immunotherapy of cancer [ 162 ], indicating the need for a careful assessment of therapeutic interventions to enhance the synergy of diverse tumor-infiltrating immune cell populations in vivo. An intriguing consistent strategy is that of switching TGF-β from an immunosuppressive cytokine into a T cell stimulant.…”