Regulating Intratumoral Leukocytes to Improve Response to Chemotherapy

项目摘要 大多数患有实体恶性肿瘤的患者接受辅助化疗方案， 新辅助治疗。对化疗的反应不仅仅取决于存在的基因组畸变 在肿瘤内，因为它也取决于细胞毒性淋巴细胞的浸润和效应功能， 在多种癌症中，CD 8 + T细胞浸润与缓解率具有强临床相关性， 支持来自可植入小鼠肿瘤模型的功能作用的证据。增强CD 8 + T细胞 因此，化疗期间的缓解有可能改善病理完全缓解率， 延长患者生存期。我们最近使用转基因小鼠模型证明了乳腺癌 肿瘤相关巨噬细胞消除CD 8 + T细胞依赖性应答的癌 化疗在未发表的工作中，我们现在已经确定这种抑制活性来自于 产生白细胞介素10（IL 10），因为巨噬细胞是肿瘤内白细胞介素10的主要来源， IL 10受体（IL 10 R）阻滞剂模仿化疗期间巨噬细胞拮抗剂的作用 反应虽然白细胞介素10不直接抑制CD 8 + T细胞增殖或功能，但我们观察到， 用抗肿瘤药物治疗后肿瘤内树突状细胞浸润和白细胞介素12表达增加 巨噬细胞拮抗剂联合化疗。因此，我们假设白细胞介素10 抑制化疗诱导的细胞死亡后树突细胞的活化，从而防止 肿瘤内CD 8 + T细胞的再活化，并提供一个易于处理的目标，以改善免疫反应， 化疗为了检验这些假设，我们提出了以下具体目标： 肿瘤内树突状细胞活化在IL-10受体介导化疗反应中意义 阻断;确定肿瘤内相对于募集的CD 8 + T细胞在介导免疫应答中的功能贡献。 IL 10 R阻断后对化疗的反应;并比较抗肿瘤免疫反应的持久性 IL 10 R阻断和化疗联合免疫检查点阻断与联合免疫检查点阻断后， 刺激激动剂。

PROJECT SUMMARY The majority of patients with solid malignancies undergo chemotherapeutic regimens either in the adjuvant or neoadjuvant setting. Response to chemotherapy is not solely dependent upon the genomic aberrations present within tumors, as it is also contingent upon the infiltration and effector function of cytotoxic lymphocytes, based upon the strong clinical association of CD8+ T cell infiltration with response rates in multiple carcinomas, and supporting evidence of a functional role from implantable mouse tumor models. Enhancing the CD8+ T cell response during chemotherapy therefore has the potential to improve pathologic complete response rates and extend patient survival. We have recently demonstrated using a transgenic mouse model of mammary carcinoma that tumor-associated macrophages abrogate the CD8+ T cell-dependent response during chemotherapy. In unpublished work, we have now identified that this suppressive activity is derived from production of interleukin 10 (IL10), as macrophages are the primary source of interleukin 10 within tumors, and IL10 receptor (IL10R) blockade phenocopies the effects of macrophage antagonists during a chemotherapeutic response. While interleukin 10 does not directly suppress CD8+ T cell proliferation or function, we observe increased infiltration of intratumoral dendritic cells and expression of interleukin 12 following treatment with macrophage antagonists in combination chemotherapy. We therefore hypothesize that interleukin 10 suppresses activation of dendritic cells following chemotherapy-induced cell death, thereby preventing reactivation of intratumoral CD8+ T cells and offering a tractable target for improving immune responses during chemotherapy. To test these hypotheses we propose the following specific aims: Determine the functional significance of intratumoral dendritic cell activation in regulating response to chemotherapy following IL10R blockade; determine the functional contribution of intratumoral versus recruited CD8+ T cells in mediating response to chemotherapy following IL10R blockade; and compare durability of anti-tumor immune responses following IL10R blockade and chemotherapy in combination with immune-checkpoint blockade versus co- stimulatory agonists.