Regulating Intratumoral Leukocytes to Improve Response to Chemotherapy

描述（由申请人提供）：大多数实体恶性肿瘤患者接受辅助或新辅助化疗方案。对化疗的反应不仅取决于肿瘤内存在的基因组畸变，还取决于细胞毒性淋巴细胞的浸润和效应功能，这是基于CD8+ T细胞浸润与多种癌症反应率的强烈临床关联，以及植入式小鼠肿瘤模型的功能作用的支持证据。因此，在化疗期间增强CD8+ T细胞反应有可能提高病理完全缓解率并延长患者生存期。我们最近使用转基因乳腺癌小鼠模型证明，肿瘤相关巨噬细胞在化疗期间消除了CD8+ T细胞依赖性反应。在未发表的工作中，我们现在已经确定这种抑制活性来源于白细胞介素10 （IL10）的产生，因为巨噬细胞是肿瘤中白细胞介素10的主要来源，IL10受体（IL10R）阻断在化疗反应期间表型上复制了巨噬细胞拮抗剂的作用。虽然白细胞介素10不直接抑制CD8+ T细胞的增殖或功能，但我们观察到在联合化疗中巨噬细胞拮抗剂治疗后，肿瘤内树突状细胞的浸润和白细胞介素12的表达增加。因此，我们假设白细胞介素10在化疗诱导的细胞死亡后抑制树突状细胞的活化，从而阻止肿瘤内CD8+ T细胞的再活化，并为改善化疗期间的免疫反应提供了一个可控制的靶点。为了验证这些假设，我们提出以下具体目标：确定肿瘤内树突状细胞激活在调节肿瘤细胞凋亡中的功能意义

DESCRIPTION (provided by applicant): 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 In unpublished work, we have now identified that this suppressive activity is derived from production of interleukin 10 (IL10), as macrophages are the primary source of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.