Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with a low 5-year survival rate and is associated with poor response to therapy. Elevated expression of the myeloid-specific hematopoietic cell kinase (HCK) is observed in PDAC and correlates with reduced patient survival. To determine whether aberrant HCK signaling in myeloid cells is involved in PDAC growth and metastasis, we established orthotopic and intrasplenic PDAC tumors in wild-type and HCK knockout mice. Genetic ablation of HCK impaired PDAC growth and metastasis by inducing an immune-stimulatory endotype in myeloid cells, which in turn reduced the desmoplastic microenvironment and enhanced cytotoxic effector cell infiltration. Consequently, genetic ablation or therapeutic inhibition of HCK minimized metastatic spread, enhanced the efficacy of chemotherapy, and overcame resistance to anti-PD1, anti-CTLA4, or stimulatory anti-CD40 immunotherapy. Our results provide strong rationale for HCK to be developed as a therapeutic target to improve the response of PDAC to chemo- and immunotherapy.

胰腺导管腺癌 (PDAC) 是一种侵袭性疾病，5 年生存率低，并且与治疗反应差有关。在 PDAC 中观察到骨髓特异性造血细胞激酶 (HCK) 的表达升高，并与患者存活率降低相关。为了确定骨髓细胞中异常的 HCK 信号传导是否参与 PDAC 生长和转移，我们在野生型和 HCK 敲除小鼠中建立了原位和脾内 PDAC 肿瘤。HCK 的基因消融通过在骨髓细胞中诱导免疫刺激性内型来损害 PDAC 的生长和转移，这反过来又减少了促纤维增生微环境并增强了细胞毒性效应细胞的浸润。因此，HCK 的基因消融或治疗性抑制最大限度地减少了转移扩散，增强了化疗的功效，并克服了对抗 PD1、抗 CTLA4 或刺激性抗 CD40 免疫疗法的耐药性。我们的结果为将 HCK 开发为改善 PDAC 对化疗和免疫治疗反应的治疗靶点提供了强有力的理由。