Role of immune regulation in colorectal cancer chemotherapeutic response

项目总结 结直肠癌(CRC)是美国癌症死亡的第二大原因。 传统的细胞毒性化疗仍然是晚期疾病的主要治疗方式 延长总生存期，但不同患者的临床反应有很大差异。最广泛的 结直肠癌常用的化疗方案是以5-氟尿嘧啶(5-FU)为主干的化疗方案。这个 5-FU的作用已经在体外和免疫缺陷小鼠中得到了广泛的研究。然而，什么？ 5-FU在体内免疫活性环境中的抗癌效果仍然知之甚少。 对这些问题的了解对于制定更有效和/或毒性更低的战略至关重要 CRC。众所周知，癌细胞在体外对5-FU的内在敏感性可以部分解释 体内对5-FU的反应性，其潜在模型是对于本质敏感的癌症，5-FU 主要通过对癌细胞的直接细胞毒性来减轻肿瘤负担。然而，无论这是不是 常规模型在免疫活性宿主中是否准确尚不清楚。根据初步数据，我们 建议测试5-FU在免疫活性环境中如何有效的修订模型：5-FU诱导 减轻肿瘤负担需要两个组成部分，即癌细胞对药物的内在敏感性 启动反应和免疫调节的明确要求，以在减少 肿瘤负担。体内缺乏任何一种成分都会降低5-FU的疗效。我们将对修改后的版本进行测试 通过三个相辅相成的目标建立模型。第一个目标，我们将测试癌症的双重要求-- 5-FU体内有效反应的细胞内源性化疗敏感性和免疫调节。在 第二个目标，我们将确定免疫调节的分子和细胞基础 肿瘤负担。在第三个目标中，我们将研究cGAS-STING途径与 和人结肠肿瘤的化疗反应。这些研究的发现有可能 改变我们对5-FU在体内作用的理解，并在5-FU之间架起一座桥梁 有效率和抗肿瘤免疫力。该项目还有可能揭示新的预测和 结直肠癌患者的治疗策略。鉴于5-FU也用于其他恶性肿瘤(例如， 胰腺、胃、胆管、小肠、乳房、头和颈部)，我们的研究有治疗 其影响远远超出《儿童权利公约》的范围。

PROJECT SUMMARY Colorectal cancer (CRC) is the second leading cause of cancer death in the United States. Conventional cytotoxic chemotherapy remains a key treatment modality for advanced-stage disease prolonging overall survival, yet clinical responses vary substantially among patients. The most widely used chemotherapy regimens for CRC are formulated with 5-fluorouracil (5-FU) as the backbone. The effects of 5-FU have been extensively studied in vitro and in immunodeficient mice. However, what underlies 5-FU’s anti-cancer efficacy in vivo in immunocompetent settings remains poorly understood, the understanding of which will be critical for devising more effective and/or less toxic strategies against CRC. It is well recognized that cancer-cell-intrinsic sensitivity to 5-FU in vitro can partially explain responsiveness to 5-FU in vivo, with the underlying model that for intrinsically sensitive cancers, 5-FU reduces tumor burden primarily through direct cytotoxicity on cancer cells. However, whether this conventional model is accurate in immunocompetent hosts is not clear. Based on preliminary data, we propose to test a revised model for how 5-FU is effective in immunocompetent settings: 5-FU-induced reduction of tumor-burden requires two components, cancer cells’ intrinsic sensitivity to the drug to prime the response and a distinct requirement for immune modulation to play a major role in reducing tumor burden. Lacking either component will reduce 5-FU efficacy in vivo. We will test this revised model through three complementary aims. In the first aim, we will test the dual requirements of cancer- cell-intrinsic chemosensitivity and immune modulation for effective response to 5-FU in vivo. In the second aim, we will determine the molecular and cellular basis of the immune modulation that reduces tumor burden. In the third aim, we will investigate the relationship between the cGAS-STING pathway and chemotherapy response of human colon tumors. Findings from these studies have the potential to transform our understanding of how 5-FU works in vivo and build a bridge between 5-FU effectiveness and anti-tumor immunity. This project also has the potential to unveil new prognostic and therapeutic strategies for CRC patients. Given that 5-FU is also used in other malignancies (e.g., pancreas, gastric, biliary, small intestinal, breast, head and neck), our studies have treatment implications well beyond CRC.