Cell surface-tethered IL-12 repolarizes the tumor immune microenvironment to enhance the efficacy of adoptive T cell therapy

Douglas S. Jones, Jonathan D. Nardozzi, Katharine L. Sackton, Gulzar Ahmad, Esben Christensen, Lars Ringgaard, De-Kuan Chang, Ditte E. Jaehger, Jacob V. Konakondla, Martin Wiinberg, Katherine L. Stokes, Alvin Pratama, Karsten Sauer, Thomas L. Andresen*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

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Abstract

Immune-activating cytokines such as interleukin-12 (IL-12) hold strong potential for cancer immunotherapy but have been limited by high systemic toxicities. We describe here an approach to safely harness cytokine biology for adoptive cell therapy through uniform and dose-controlled tethering onto the surface of the adoptively transferred cells. Tumor-specific T cells tethered with IL-12 showed superior antitumor efficacy across multiple cell therapy models compared to conventional systemic IL-12 coadministration. Mechanistically, the IL-12-tethered T cells supported a strong safety profile by driving interferon-γ production and adoptively transferred T cell activity preferentially in the tumor. Immune profiling revealed that the tethered IL-12 reshaped the suppressive tumor immune microenvironment, including triggering a pronounced repolarization of monocytic myeloid-derived suppressor cells into activated, inflammatory effector cells that further supported antitumor activity. This tethering approach thus holds strong promise for harnessing and directing potent immunomodulatory cytokines for cell therapies while limiting systemic toxicities.
Original languageEnglish
Article numbereabi8075
JournalScience Advances
Volume8
Issue number17
Number of pages17
ISSN2375-2548
DOIs
Publication statusPublished - 2022

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