Purpose: Although immunotherapies have resulted in durable clinical responses, not all tumor types have seen substantial benefit. Extensive recruitment and accumulation of immunosuppressive myeloid cells into the tumor tissues has been postulated as a major mechanism of resistance to immunotherapies. Strategies targeting on single immunosuppressive cell type, in combination with checkpoint inhibitors, have resulted in promising outcomes in animal studies. However, compensatory actions by untargeted cells may limit the therapeutic efficacy. CD11b is highly expressed on the myeloid cell surface with an important role in their trafficking and cellular functions.In this study, we demonstrated that activation of CD11b with 15-hydroxy-6α,12-epoxy-7β,10αH,11βH-spiroax-4-ene-12-one (HESEO) enhanced the therapeutic efficacy of anti-PD1 treatment in the tumor model. Materials and methods: A syngeneic rectal tumor model was established. Different types of cells from the peripheral blood and tumor tissues were analyzed by flow cytometry. Real-time PCR was used to detect the gene expression. Therapeutic effects of HESEO combining with anti-PD1 antibody were assessed by the tumor model. Results: Our data demonstrated that HESEO repolarized tumor-associated macrophages and reduced the number of tumor-infiltrating immunosuppressive myeloid cells. We further demonstrated that HESEO and immunotherapy combination promoted tumor growth control in a syngeneic tumor model. Conclusions: Our results showed that HESEO improved anti-tumor T cell immunity and rendered anti-PD1 treatment effective in unresponsive tumor models, providing proof of concept for a new combination strategy involving molecular agonism of CD11b to bypass the limitations of current clinical strategies to overcome resistance to immunotherapies.

目的：尽管免疫疗法已经产生了持久的临床反应，但是并不是所有的肿瘤类型都能获得实质性的益处。免疫抑制性髓样细胞广泛募集和积累到肿瘤组织中被认为是对免疫疗法产生抗药性的主要机制。针对单一免疫抑制细胞类型的策略，结合检查点抑制剂，已在动物研究中产生了可喜的成果。但是，未靶向细胞的补偿作用可能会限制治疗效果。CD11b在髓样细胞表面高表达，在其运输和细胞功能中起重要作用。在这项研究中，我们证明了CD11b可以被15-羟基-6α，12-环氧-7β，10αH，11βH-spiroax-4激活-ene-12-one（HESEO）在肿瘤模型中增强了抗PD1治疗的疗效。材料与方法：建立同基因直肠肿瘤模型。通过流式细胞术分析来自外周血和肿瘤组织的不同类型的细胞。使用实时PCR检测基因表达。通过肿瘤模型评估HESEO与抗PD1抗体联合的治疗效果。结果：我们的数据表明，HESEO使与肿瘤相关的巨噬细胞复极化，并减少了肿瘤浸润性免疫抑制骨髓细胞的数量。我们进一步证明了HESEO和免疫疗法的组合在同基因肿瘤模型中促进了肿瘤生长的控制。结论： 我们的结果表明，HESEO改善了抗肿瘤T细胞免疫力，并使抗PD1治疗在无反应的肿瘤模型中有效，为涉及CD11b分子激动作用的新联合治疗策略提供了概念验证，从而绕过了目前临床对克服抗药性的限制。免疫疗法。