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Therapeutic inhibition of the SRC-kinase HCK facilitates T cell tumor infiltration and improves response to immunotherapy

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journal contribution
posted on 2022-07-27, 06:15 authored by Ashleigh PohAshleigh Poh, CG Love, David ChisangaDavid Chisanga, JH Steer, David Baloyan, M Chopin, S Nutt, J Rautela, ND Huntington, N Etemadi, Megan O'BrienMegan O'Brien, Ryan O'KeefeRyan O'Keefe, LG Ellies, C Macri, JD Mintern, L Whitehead, Gangadhara GangadharaGangadhara Gangadhara, L Boon, Ashwini ChandAshwini Chand, CA Lowell, Wei ShiWei Shi, FJ Pixley, Matthias ErnstMatthias Ernst
Although immunotherapy has revolutionized cancer treatment, many immunogenic tumors remain refractory to treatment. This can be largely attributed to an immunologically “cold” tumor microenvironment characterized by an accumulation of immunosuppressive myeloid cells and exclusion of activated T cells. Here, we demonstrate that genetic ablation or therapeutic inhibition of the myeloid-specific hematopoietic cell kinase (HCK) enables activity of antagonistic anti–programmed cell death protein 1 (anti-PD1), anti-CTLA4, or agonistic anti-CD40 immunotherapies in otherwise refractory tumors and augments response in treatment-susceptible tumors. Mechanistically, HCK ablation reprograms tumor-associated macrophages and dendritic cells toward an inflammatory endotype and enhances CD8+ T cell recruitment and activation when combined with immunotherapy in mice. Meanwhile, therapeutic inhibition of HCK in humanized mice engrafted with patient-derived xenografts counteracts tumor immunosuppression, improves T cell recruitment, and impairs tumor growth. Collectively, our results suggest that therapeutic targeting of HCK activity enhances response to immunotherapy by simultaneously stimulating immune cell activation and inhibiting the immunosuppressive tumor microenvironment.


This work was supported by National Health and Medical Research Council of Australia Project Grants 1025239, 1079257, 1081373, and 1092788 (M.E.); a National Health and Medical Research Council Investigator Grant (M. E.); a Cancer Council of Victoria Post-Doctoral Fellowship (A.R.P.); a Jack Brockhoff Foundation Early Career Research grant 4656-2019 (A.R.P.); a National Health and Medical Research Council of Australia Peter Doherty Early Career Fellowship GNT1166447 (A.R.P.); and an UC Cancer Research Coordinating Committee grant CRR-20-636450 (C.A.L.).


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Science Advances





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American Association for the Advancement of Science



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Copyright © 2022 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC), which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: