Regulating Intratumoral Leukocytes to Improve Response to Chemotherapy

描述(申请人提供)：大多数实体恶性肿瘤患者在辅助或新辅助环境下接受化疗方案。对化疗的反应不仅依赖于肿瘤内存在的基因组异常，还取决于细胞毒性淋巴细胞的渗透和效应功能，这是基于CD8+T细胞渗透与多种癌症的应答率之间的强烈临床相关性，以及从可移植的小鼠肿瘤模型中支持功能作用的证据。因此，在化疗过程中增强CD8+T细胞反应有可能提高病理完全缓解率，延长患者生存时间。我们最近利用乳腺癌转基因小鼠模型证明，在化疗期间，肿瘤相关巨噬细胞可以消除CD8+T细胞依赖的反应。在未发表的工作中，我们现在已经确认这种抑制活性来自于白介素10(IL10)的产生，因为巨噬细胞是肿瘤内白介素10的主要来源，而IL10R(IL10R)阻断巨噬细胞拮抗剂在化疗反应中的作用。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用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，我们假设白介素10抑制了化疗诱导的细胞死亡后树突状细胞的激活，从而阻止了肿瘤内CD8+T细胞的重新激活，为改善化疗期间的免疫反应提供了一个易于处理的靶点。为了验证这些假设，我们提出了以下具体目标：确定肿瘤内树突状细胞激活在调控中的功能意义 研究对象包括IL10R阻断后对化疗的反应；确定瘤内CD8+T细胞与招募的CD8+T细胞在调节IL10R阻断后化疗反应中的功能贡献；以及比较IL10R阻断后的抗肿瘤免疫反应和联合免疫检查点阻断与共刺激激动剂的抗肿瘤免疫反应的持久性。

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 In unpublished work, we have now identified that this suppressive activity is derived from production of interleukin 10 (IL10), as macrophages are the primary source of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