The myeloid SRC family kinase HCK regulates breast cancer growth by activating tumor-associated macrophage-led invasion and inhibiting cytotoxic T cell activity.

Introduction: The normal developmental and homeostatic roles of tissue resident macrophages are subverted in tumor-associated macrophages to promote tumor progression. Pro-tumoral macrophage activities include immune suppression and promotion of invasion and metastasis. While the myeloid Src family kinase HCK is known to regulate immune evasion, here we show that HCK promotes growth of an aggressively invasive mammary tumor through activation of macrophage motility and invasive capacity. Method: We used the Py8119 mouse mammary tumor model to investigate the role of Hck activity in tumor growth through therapeutic inhibition and genetic modification. Single cell RNA sequencing and immunohistochemistry approaches were used to investigate changes to the immune compartment. Results: Loss of HCK activity reduced the growth of Py8119 mammary tumors by 70-80% while excessive HCK activity increased growth four-fold. Consistent with a role for HCK in macrophage invasiveness, plasma membrane-associated Src family kinase activity at the tumor margins was lost in the absence of HCK. Regarding immune evasion, HCK-deficient tumors contained increased CD8 Conclusion: This study provides evidence that HCK activity in TAMs enhances tumour growth via promotion of invasive behaviour as well as suppression of anti-tumor immunity. These findings highlight HCK as a promising therapeutic target to limit tumor progression.