Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
Breast Tumor Immunology Laboratory, Susan F. Smith Center for Women's Cancers, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
J Immunother Cancer. 2019 Jul 30;7(1):199. doi: 10.1186/s40425-019-0654-5.
Despite major advancements in immunotherapy among a number of solid tumors, response rates among ovarian cancer patients remain modest. Standard treatment for ovarian cancer is still surgery followed by taxane- and platinum-based chemotherapy. Thus, there is an urgent need to develop novel treatment options for clinical translation.
Our approach was to analyze the effects of standard chemotherapy in the tumor microenvironment of mice harboring orthotopic, syngeneic ID8-Vegf-Defb29 ovarian tumors in order to mechanistically determine a complementary immunotherapy combination. Specifically, we interrogated the molecular and cellular consequences of chemotherapy by analyzing gene expression and flow cytometry data.
These data show that there is an immunosuppressive shift in the myeloid compartment, with increased expression of IL-10 and ARG1, but no activation of CD3 T cells shortly after chemotherapy treatment. We therefore selected immunotherapies that target both the innate and adaptive arms of the immune system. Survival studies revealed that standard chemotherapy was complemented most effectively by a combination of anti-IL-10, 2'3'-cGAMP, and anti-PD-L1. Immunotherapy dramatically decreased the immunosuppressive myeloid population while chemotherapy effectively activated dendritic cells. Together, combination treatment increased the number of activated T and dendritic cells as well as expression of cytotoxic factors. It was also determined that the immunotherapy had to be administered concurrently with the chemotherapy to reverse the acute immunosuppression caused by chemotherapy. Mechanistic studies revealed that antitumor immunity in this context was driven by CD4 T cells, which acquired a highly activated phenotype. Our data suggest that these CD4 T cells can kill cancer cells directly via granzyme B-mediated cytotoxicity. Finally, we showed that this combination therapy is also effective at delaying tumor growth substantially in an aggressive model of lung cancer, which is also treated clinically with taxane- and platinum-based chemotherapy.
This work highlights the importance of CD4 T cells in tumor immunology. Furthermore, the data support the initiation of clinical trials in ovarian cancer that target both innate and adaptive immunity, with a focus on optimizing dosing schedules.
尽管在许多实体肿瘤的免疫治疗方面取得了重大进展，但卵巢癌患者的反应率仍然不高。卵巢癌的标准治疗仍是手术加紫杉烷类和铂类化疗。因此，迫切需要开发新的治疗选择用于临床转化。
我们的方法是分析标准化疗在携带同源、同源 ID8-Vegf-Defb29 卵巢肿瘤的小鼠肿瘤微环境中的作用，以从机制上确定互补的免疫治疗组合。具体来说，我们通过分析基因表达和流式细胞术数据来研究化疗的分子和细胞后果。
这些数据表明，在化疗后不久，髓系细胞发生免疫抑制转移，IL-10 和 ARG1 的表达增加，但 CD3 T 细胞没有激活。因此，我们选择了针对固有免疫和适应性免疫系统的免疫疗法。生存研究表明，标准化疗与抗 IL-10、2'3'-cGAMP 和抗 PD-L1 的联合治疗效果最佳。免疫治疗显著减少了免疫抑制性髓系细胞，而化疗有效地激活了树突状细胞。联合治疗增加了激活的 T 细胞和树突状细胞的数量以及细胞毒性因子的表达。还确定免疫治疗必须与化疗同时进行，以逆转化疗引起的急性免疫抑制。机制研究表明，在这种情况下，抗肿瘤免疫是由获得高度激活表型的 CD4 T 细胞驱动的。我们的数据表明，这些 CD4 T 细胞可以通过颗粒酶 B 介导的细胞毒性直接杀死癌细胞。最后，我们表明，这种联合疗法在一种侵袭性肺癌模型中也能显著延迟肿瘤生长，该模型也在临床上用紫杉烷类和铂类化疗治疗。
这项工作强调了 CD4 T 细胞在肿瘤免疫学中的重要性。此外，这些数据支持在卵巢癌中开展针对固有和适应性免疫的临床试验，重点是优化剂量方案。
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