Pancreatic ductal adenocarcinoma (PDAC) resists conventional chemo/radiation and immunotherapy. In PDAC, oncogenic KRAS (KRAS*) drives glycolysis in cancer cells to consume available glucose and produce abundant lactate, creating profound immune suppression in the tumor microenvironment. Here, we combined KRAS* inhibition with agents targeting the major arms of the immunity cycle: CXCR1/2 inhibitor for myeloid cells, antagonistic anti-LAG3 antibody for T cells, and agonistic anti-41BB antibody for dendritic cells. This combination elicited robust anti-tumor regression in iKPC mice bearing large autochthonous tumors. While untreated mice succumbed within 3 weeks, sustained treatment led to durable complete tumor regression and prolonged survival in 36% of mice at 6 months. Mechanistic analyses revealed enhanced T cell infiltration and activation, depletion of immunosuppressive myeloid cells, and increased antigen cross-presentation by dendritic cells within the tumor core. These findings highlight the promise of KRAS* inhibitors alongside immunotherapy as a potential PDAC treatment avenue, warranting clinical investigation.

中文翻译：

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KRAS 抑制和免疫治疗相结合，在本地 PDAC 模型中产生持久的完全反应


胰腺导管腺癌（PDAC）对传统化疗/放疗和免疫疗法具有抵抗力。在 PDAC 中，致癌 KRAS (KRAS*) 驱动癌细胞中的糖酵解，消耗可用的葡萄糖并产生丰富的乳酸，从而在肿瘤微环境中产生深刻的免疫抑制。在这里，我们将 KRAS* 抑制与针对免疫周期主要武器的药物相结合：针对骨髓细胞的 CXCR1/2 抑制剂、针对 T 细胞的拮抗性抗 LAG3 抗体以及针对树突状细胞的激动性抗 41BB 抗体。这种组合在携带大的原生肿瘤的 iKPC 小鼠中引发了强大的抗肿瘤消退。虽然未经治疗的小鼠在 3 周内死亡，但持续治疗导致 36% 的小鼠肿瘤持久完全消退，并在 6 个月时延长了生存期。机制分析揭示了 T 细胞浸润和激活增强、免疫抑制性骨髓细胞耗竭以及肿瘤核心内树突状细胞抗原交叉呈递增加。这些发现凸显了 KRAS* 抑制剂与免疫疗法一起作为潜在 PDAC 治疗途径的前景，值得临床研究。