IL-12/18/21 pre-activation enhances the anti-tumor efficacy of expanded γδT cells and overcomes resistance to anti-PD-L1 treatment

Liu, H.; Teo, H. Y.; Song, Y.; Yong, K. S. M.; Liu, Y.; Mei, Y.; Hanafi, Z. B.; Zhu, Y.; Gascoigne, N. R. J.; Chen, Q.

doi:10.1101/2022.08.11.503563

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bioRxiv · 10.1101/2022.08.11.503563

IL-12/18/21 pre-activation enhances the anti-tumor efficacy of expanded γδT cells and overcomes resistance to anti-PD-L1 treatment

Liu, H.·Teo, H. Y.·Song, Y.·Yong, K. S. M.·Liu, Y.·Mei, Y.·Hanafi, Z. B.·Zhu, Y.·Gascoigne, N. R. J.·Chen, Q.

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Abstract

{gamma}{delta}T cells are promising candidates for cellular immunotherapy due to their immune regulation through cytokine production and MHC-independent direct cytotoxicity against a broad spectrum of tumors. However, current {gamma}{delta}T cell-based cancer immunotherapy has limited efficacies and novel strategies are needed to improve its clinical outcomes. Here, we report that cytokine pre-treatment with IL-12/18, IL-12/15/18, IL-12/18/21 and IL-12/15/18/21 could effectively enhance the activation and cytotoxicity of in vitro expanded murine and human {gamma}{delta}T cells. However, only adoptive transfer of IL-12/18/21 pre-activated {gamma}{delta}T cells significantly inhibited tumor growth in a murine melanoma model and a hepatocellular carcinoma model. Both IL-12/18/21 pre-activated antibody-expanded and zoledronate-expanded human {gamma}{delta}T cells effectively controlled tumor growth in a humanized mouse model. IL-12/18/21 pre-activation promoted {gamma}{delta}T cell proliferation and cytokine production in vivo and enhanced IFN-{gamma} and TNF- production, as well as granzyme B expression by endogenous CD8+ T cells in a cell-cell contact dependent manner. Furthermore, the adoptive transfer of IL-12/18/21 pre-activated {gamma}{delta}T cells could overcome the resistance to anti-PD-L1 therapy, and the combination therapy had a synergistic effect on the therapeutic outcomes. Moreover, the enhanced anti-tumor function of adoptively transferred IL-12/18/21 pre-activated {gamma}{delta}T cells was largely diminished in the absent of endogenous CD8+T cells when administered alone or in combination with anti-PD-L1, suggesting a CD8+T cell-dependent mechanism. Taken together, IL-12/18/21 pre-activation could promote {gamma}{delta}T cell anti-tumor function and overcome the resistance to checkpoint blockade therapy, indicating an effective combinational cancer immunotherapeutic strategy. SynopsisO_LIIL-12/18/21 pre-activation enhances the anti-tumor efficacy of adoptively transferred {gamma}{delta}T cells by promoting its proliferation, activation, and cytotoxicity, as well as activating endogenous CD8+ T cells. C_LIO_LIAdoptive transfer of IL-12/18/21 pre-activated {gamma}{delta}T cells could overcome the resistance to anti-PD-L1 therapy, indicating an effective combinational cancer immunotherapeutic strategy. C_LI

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Liu, H., Teo, H. Y., Song, Y., Yong, K. S. M., Liu, Y., Mei, Y., Hanafi, Z. B., Zhu, Y., Gascoigne, N. R. J., Chen, Q.. 2022-08-13. IL-12/18/21 pre-activation enhances the anti-tumor efficacy of expanded γδT cells and overcomes resistance to anti-PD-L1 treatment. https://doi.org/10.1101/2022.08.11.503563

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