In the Absence of a TCR Signal IL-2/IL-12/18-Stimulated γδ T Cells Demonstrate Potent Anti-Tumoral Function Through Direct Killing and Senescence Induction in Cancer Cells.

Abundant IFN-gamma secretion, potent cytotoxicity, and major histocompatibility complex-independent targeting of a large spectrum of tumors make gamma delta T cells attractive candidates for cancer immunotherapy. Upon tumor recognition through the T-cell receptor (TCR), NK-receptors, or NKG2D, gamma delta T cells generate the pro-inflammatory cytokines TNF-alpha and IFN-gamma, or granzymes and perforin that mediate cellular apoptosis. Despite these favorable potentials, most clinical trials testing the adoptive transfer of pharmacologically TCR-targeted and expanded gamma delta T cells resulted in a limited response. Recently, the TCR-independent activation of gamma delta T cells was identified. However, the modulation of gamma delta T cell's effector functions solely by cytokines remains to be elucidated. In the present study, we systematically analyzed the impact of IL-2, IL-12, and IL-18 in parallel with TCR stimulation on proliferation, cytokine production, and anti-tumor activity of gamma delta T cells. Our results demonstrate that IL-12 and IL-18, when combined, constitute the most potent stimulus to enhance anti-tumor activity and induce proliferation and IFN-gamma production by gamma delta T cells in the absence of TCR signaling. Intriguingly, stimulation with IL-12 and IL-18 without TCR stimulus induces a comparable degree of anti-tumor activity in gamma delta T cells to TCR crosslinking by killing tumor cells and driving cancer cells into senescence. These findings approve the use of IL-12/IL-18-stimulated gamma delta T cells for adoptive cell therapy to boost anti-tumor activity by gamma delta T cells.