Blockade of histamine receptor H1 augments immune checkpoint therapy by enhancing MHC-I expression in pancreatic cancer cells

Although immune checkpoint blockade (ICB) therapy has proven to be extremely effective in managing certain cancers, its efficacy in pancreatic ductal adenocarcinoma (PDAC) remains limited. Previous studies have indicated that histamine and histamine receptor H1 (HRH1) can suppress immunity by affecting immune cells. This study uncovered an unexplored role of HRH1 intrinsic to tumor cells in PDAC. When HRH1 specific to tumor cells was inhibited in PDAC mouse models, there was a noticeable increase in MHC-I expression in these cells via the activation of cholesterol biosynthesis signaling. This augmented the infiltration and efficacy of cytotoxic CD8+ T cells, synergizing anticancer immunity and mitigating resistance to ICB treatment. Our results highlight that HRH1 plays an immunosuppressive role in cancer cells. Consequently, HRH1 intervention may be a promising method to amplify the responsiveness of PDAC to immunotherapy. Human cell lines (MIA PaCa-2 and KP-2) were treated with Az or H2O.

尽管免疫检查点阻断（immune checkpoint blockade, ICB）疗法在部分癌症的临床管理中已被证实极具疗效，但该疗法在胰腺导管腺癌（pancreatic ductal adenocarcinoma, PDAC）中的治疗效果仍十分有限。既往研究显示，组胺（histamine）与组胺H1受体（histamine receptor H1, HRH1）可通过调控免疫细胞发挥免疫抑制功能。本研究揭示了胰腺导管腺癌中肿瘤细胞固有组胺H1受体的一种尚未被探索的作用。在胰腺导管腺癌小鼠模型中抑制肿瘤细胞特异性表达的组胺H1受体后，可通过激活胆固醇生物合成信号通路，显著上调这些肿瘤细胞的主要组织相容性复合体I类（MHC-I）表达水平。这一变化增强了细胞毒性CD8+ T细胞的浸润与抗肿瘤效能，协同强化了抗癌免疫应答并缓解了对免疫检查点阻断疗法的耐药性。本研究结果证实，组胺H1受体在肿瘤细胞中发挥免疫抑制作用。因此，靶向组胺H1受体的干预策略或可成为增强胰腺导管腺癌对免疫疗法响应性的潜在有效手段。本研究采用Az或H₂O处理人源细胞系MIA PaCa-2与KP-2。