In the past decade, the field of immunotherapy has witnessed remarkable advances for the treatment of cancer patients. However, while immune-checkpoint blockade has shown impressive success in cancers such as melanoma and renal-cell carcinoma, some patients do not respond to treatment. This is largely attributed to an immunosuppressive tumour microenvironment characterized by the infiltration of alternatively-activated “tumour-promoting” macrophages.
Elevated expression of the myeloid-specific Src family kinase Hematopoietic Cell Kinase (HCK) occurs in a majority of solid malignancies and correlates with poor patient survival. We have previously shown that HCK promotes tumour growth by enhancing macrophage polarisation towards an immunosuppressive alternatively-activated endotype. Accordingly, inhibition of HCK signalling with a small molecule HCK inhibitor reduced the growth of endogenous mouse and human xenograft tumours by impairing alternative macrophage polarisation.
Using four models of primary and metastatic cancer (gastric, colon, breast and melanoma), we now demonstrate that genetic ablation of HCK or pharmacologic inhibition of its activity further enhances the anti-tumor effects conferred by single agent immunotherapies based on anti-PD1, anti-CTLA4 or agonistic-CD40 antibodies. Mechanistically, HCK inhibition reverses the immunosuppressive tumour microenvironment created by alternatively-activated macrophages, and “re-educates” these cells towards an inflammatory and activated endotype. Notably, HCK knock-out mice treated with each of the immunotherapies also showed an increase in tumour cell apoptosis attributed to the enhanced trafficking of effector CD8+ T-cells and NK cells into the tumour core, and their increased production of cytotoxic molecules including IL12, Perforin and Granzyme B.
Taken together, HCK represents a promising therapeutic target to reverse the immunosuppressive tumour microenvironment of solid cancers and improve the efficacy of immunotherapy.