Combination therapy targeting both innate and adaptive immunity improves survival in a preclinical model of ovarian cancer

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Dokumentart: Dissertation
Date: 2021-05-17
Language: English
Faculty: 7 Mathematisch-Naturwissenschaftliche Fakultät
Department: Biochemie
Advisor: Stevanovic, Stefan (Prof. Dr.)
Day of Oral Examination: 2019-05-17
DDC Classifikation: 500 - Natural sciences and mathematics
570 - Life sciences; biology
Keywords: Eierstockkrebs , Tumorimmunologie , Kombinationstherapie
Other Keywords:
Ovarian cancer
cancer immunotherapy
combination therapy
CD4+ T cells
innate immunity
License: Publishing license including print on demand
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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. Chemotherapy together with various single immunotherapies was not able to increase survival in this model. We therefore selected immunotherapy combinations 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. Further analysis of human samples revealed that there is also downregulation of immune function after treatment with chemotherapy. 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.

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