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

Ashleigh R. Poh, Christopher G. Love, David Chisanga, James H. Steer, David Baloyan, Michaël Chopin, Stephen Nutt, Jai Rautela, Nicholas D. Huntington, Nima Etemadi, Megan O’Brien, Ryan O’Keefe, Lesley G. Ellies, Christophe Macri, Justine D. Mintern, Lachlan Whitehead, Gangadhara Gangadhara, Louis Boon, Ashwini L. Chand, Clifford A. LowellWei Shi, Fiona J. Pixley, Matthias Ernst

Research output: Contribution to journalArticlepeer-review

15 Citations (Scopus)

Abstract

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.

Original languageEnglish
Article numbereabl7882
JournalScience Advances
Volume8
Issue number25
DOIs
Publication statusPublished - Jun 2022

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