A β-1,3/1,6-glucan from Durvillaea Antarctica enhances anti-tumor effects of immune checkpoint inhibitor antibodies

Immunotherapy has emerged as a frontline approach in cancer management, aiming to enhance the adaptive immune response against tumors. However, its limited efficacy across a narrow range of tumor types necessitates the exploration of novel strategies that target innate immunity. Therapeutic modulation of pattern recognition receptors (PRRs) and innate immune cells holds promise in tumor eradication. β-glucan, a pathogen-associated molecular pattern (PAMP), acts as an immunostimulator, bridging the innate and adaptive immune responses. It exhibits low toxicity and high compatibility with various antitumor strategies. Plenty of clinical trials are ongoing to evaluate β-glucan-based cancer immunotherapy and shows promising clinical benefits across multiple cancer types. A soluble β-1,3/1,6-glucan with high purity from Durvillaea Antarctica (BG136) was reported previously by our group to exhibit pan antitumor effects alone as an immune stimulator. In current study, we proved the antitumor activity of BG136 in combination with anti-PD-1 antibodies in MC38 syngeneic tumor model in vivo. Integrated transcriptomic and metabolomic analyses suggest that BG136 enhances the antitumor immunity of anti-PD-1 antibodies by reprogramming tumor microenvironment to more proinflammatory status. There are more innate and adaptive immune cell infiltration and activation, enhanced lipid metabolism, decreased ascorbate and aldarate metabolism. These findings provide mechanistic insights supporting the potent antitumor efficacy of BG136 in combination with immune checkpoint inhibitor antibodies. In order to assess the in vivo antitumor efficacy of BG136, a highly purified soluble β-1,3/1,6-glucan extracted from Antarctic rhododendron, in combination with anti-PD-1 antibody, we developed a mouse MC38 syngeneic tumor model. Subsequently, tumor blocks from various treatment groups, comprising vector control and BG136 alone, were collected for gene expression profiling analysis.

免疫治疗已成为癌症管理的一线治疗手段，旨在增强针对肿瘤的适应性免疫应答。然而，其仅在少数肿瘤类型中疗效有限，因此亟需探索靶向先天免疫的新型抗肿瘤策略。模式识别受体（pattern recognition receptors，PRRs）与先天免疫细胞的治疗性调控，在肿瘤清除领域展现出巨大应用前景。β-葡聚糖作为一类病原相关分子模式（pathogen-associated molecular pattern，PAMP），可作为免疫刺激剂，搭建起先天免疫与适应性免疫之间的桥梁。该物质毒性低，且与多种抗肿瘤策略具备良好兼容性。目前已有多项临床试验正在评估基于β-葡聚糖的癌症免疫治疗方案，并在多种肿瘤类型中展现出颇具潜力的临床获益。本研究团队此前曾报道，从南极翅藻（Durvillaea Antarctica）中提取的高纯度可溶性β-1,3/1,6-葡聚糖（BG136），单独作为免疫刺激剂时即可发挥泛抗肿瘤效应。在本研究中，我们验证了BG136与抗PD-1抗体联合使用时，在体内MC38同基因肿瘤模型中的抗肿瘤活性。整合转录组学与代谢组学分析结果表明，BG136可通过将肿瘤微环境重编程为更具促炎性的状态，增强抗PD-1抗体的抗肿瘤免疫效应。该联合治疗可促进更多先天与适应性免疫细胞的浸润与激活，增强脂质代谢水平，并下调抗坏血酸和醛糖酸代谢通路。上述发现为BG136与免疫检查点抑制剂抗体联合使用的强效抗肿瘤功效提供了机制层面的科学阐释。为评估从南极杜鹃花（Antarctic rhododendron）中提取的高纯度可溶性β-1,3/1,6-葡聚糖BG136与抗PD-1抗体联合使用的体内抗肿瘤疗效，我们构建了小鼠MC38同基因肿瘤模型。随后，我们收集了包括载体对照组与BG136单独给药组在内的各治疗组的肿瘤组织块，用于基因表达谱分析。