Targeting the Immunosuppressive Tumor Microenvironment for Colorectal Cancer Treatment

项目摘要/摘要 尽管结直肠癌(CRC)的治疗有了显著改善，但患有结直肠癌的患者的预后 转移性结直肠癌(MCRC)仍然很差，中位总生存期约为30个月。 免疫检查点阻断(ICB)等免疫疗法代表了一种新的治疗方法 多种癌症，包括微卫星不稳定性高的mCRC(MSI-H)。然而，ICB疗法几乎没有显示出什么 或在大约95%的微卫星稳定(MSS)mCRC患者中没有临床活动。我们和其他人 已经表明，给予生酮饮食(KD)或酮体β-羟基丁酸酯(βHB)， 增强ICB对结直肠癌小鼠肿瘤模型的抗癌作用。然而，KD/βHb是否可以改善 ICB治疗伴有MSS的CRCs尚不清楚。此外，酮的发生改变对细胞的影响 免疫抑制肿瘤微环境(TME)仍有待定义，并代表着我们在 对肿瘤免疫耐药的认识。 肿瘤相关成纤维细胞(CAF)是肿瘤间质细胞的主要成分，在肿瘤的发生、发展过程中发挥着重要作用。 抑制肿瘤的TME。我们已经证明，下调的酮类生成是CRC TME的一个标志。激活 癌基因信号转导(如WNT和KRAS)可减少癌组织中酮的生成。恢复生酮作用 抑制CAF的有氧糖酵解活性并抑制组蛋白脱乙酰酶1(HDAC1/KLF5)依赖的CAF 增殖和细胞因子的表达和分泌。重要的是，我们证明了KD改善了 免疫抑制的TME，表现为CD8+T细胞和NK细胞浸润增加，M2减少 巨噬细胞群，并增强ICB的疗效。我们的发现证明了一种以前未知的 TME和HAVE中新生酮生成、代谢改变和CAF功能下调的关系 将癌酮生成确定为潜在的免疫治疗靶点。基于这些新发现，我们 假说下调的酮生成有助于细胞的增殖和免疫抑制作用 因此，对CRC TME进行重新编程，从而导致ICB抵抗和CRC进展。我们的长期合作 目标是识别癌症和/或间质间隔内的异常代谢，这些代谢可用于 提高多发性结直肠癌患者的治疗水平。为了检验我们的中心假设，我们收集了一个高度 在结直肠癌进展和治疗、肿瘤代谢、肿瘤方面拥有丰富专业知识的协作团队 免疫和肿瘤酮的发生，以及计划中的实验，以确定改变 结直肠癌免疫抑制TME的生酮作用，阐明CAF代谢的生酮调控， TME中的增殖和功能潜能，并确定靶向生酮代谢对TME的影响 ICB治疗结直肠癌的疗效观察最终，我们的发现将：i)彻底改变我们的CRC TME概念，并 免疫耐受；ii)大大推进了关于KD/βHb影响的范例；以及iii)可以提供 通过靶向异常的生酮代谢治疗结直肠癌的新策略。

Project Summary/Abstract Despite notable improvements in colorectal cancer (CRC) treatment, the prognosis of patients with metastatic CRC (mCRC) remains poor, with a median overall survival of approximately 30 months. Immunotherapy such as immune checkpoint blockade (ICB) represents a novel therapeutic approach for a variety of cancers including mCRC with microsatellite instability-high (MSI-H). However, ICB therapy shows little or no clinical activity in approximately 95% of patients with microsatellite-stable (MSS) mCRC. We and others have shown that administration of either a ketogenic diet (KD) or the ketone body β-hydroxybutyrate (βHB), enhances the anticancer effects of ICB for CRC in mouse tumor models. However, whether KD/βHB can improve ICB therapy for CRCs with MSS is not known. Moreover, the impact of altered ketogenesis on the immunosuppressive tumor microenvironment (TME) remains to be defined and represents a major gap in our understanding of tumor immunoresistance. Cancer associated fibroblasts (CAFs), the major component of tumor stromal cells, play a critical role in the tumor suppressive TME. We have shown that downregulated ketogenesis is a hallmark in CRC TME. Activation of oncogenic signaling (e.g., WNT and KRAS) decreases ketogenesis in CRCs. Restoration of ketogenesis inhibits aerobic glycolytic activity in CAFs and inhibits histone deacetylase 1 (HDAC1)/KLF5 dependent CAF proliferation and cytokine expression and secretion. Importantly, we showed that KD improves the immunosuppressive TME, as noted by increased CD8+ T cell and NK cell infiltration and decreased M2 macrophage populations, and enhances the efficacy of ICB. Our findings demonstrate a previously unknown association of downregulated de novo ketogenesis, metabolic alteration and CAF functions in the TME and have identified cancer ketogenesis as a potential immunotherapeutic target. Based on these novel findings, we hypothesize that downregulated ketogenesis contributes to the proliferation and immunosuppressive effects of CAFs and thus, reprograms the CRC TME, which leads to ICB resistance and CRC progression. Our long-term goal is to identify aberrant metabolism within the cancer and/or stromal compartments that can be used to improve the treatment of patients with mCRC. To examine our central hypothesis, we have assembled a highly collaborative team with significant expertise in CRC progression and treatment, tumor metabolism, tumor immunity and neoplastic ketogenesis, and planned experiments which will determine the impact of alterations of ketogenesis on the immunosuppressive TME in CRC, delineate ketogenic control of CAF metabolism, proliferation, and functional potency in the TME, and define the impact of targeting ketogenic metabolism on the efficacy of ICB for CRC. Ultimately, our findings will: i) revolutionize our concept of CRC TME and immunoresistance; ii) significantly advance paradigms regarding the effects of KD/βHB; and iii) may provide a novel CRC treatment strategy by targeting dysregulated ketogenic metabolism.