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The immune-modulating effects of PFKFB3 inhibition in a syngeneic ovarian cancer model
The immune-modulating effects of PFKFB3 inhibition in a syngeneic ovarian cancer model
Background: Despite significant advances in surgery and chemotherapy, ovarian cancer remains the leading cause of death among gynecological malignancies. In an effort to establish new therapies, the focus has shifted toward restricting cancer metabolism. A key regulatory enzyme, PFKFB3, is overexpressed in OC and plays an important role in promoting tumor cell growth. Targeting glycolysis via selective PFKFB3 inhibition has shown promising results in pre-clinical studies. Nevertheless, its effects on the hosts` ability to initiate a potent anti-tumor immune response remain unknown. In this study, we describe the effects of PFK-158, a novel selective molecule inhibitor of PFKFB3, on the immune profile of mice using a syngeneic ovarian cancer model. Methods: We investigated the anti-cancer activity and immune-modulating effects of PFK-158 treatment in vitro, ex vivo, and in vivo. The focus of this study has been the adaptive immune system and more specifically, the T cell-mediated immune response, being the most relevant prognostic factor in OC survival. Proliferation and metabolomic analysis were performed on serous ovarian cancer mimicking STOSE cells as well as murine T cells purified from splenic tissue. T cell secretory function was assessed by flow cytometry. Lastly, a comparative analysis of tumor burden and immunologic parameters in plasma, spleens, and ascitic fluid was performed in the control and treatment groups. Results: Our study showed that PFKFB3 inhibition decreased the proliferation of malignant cells by metabolic restriction in vitro and resulted in suppressed tumor growth in vivo. PFK-158 also inhibited T cell viability, proliferation, and function as measured by cytokine release ex vivo. However, the loss of function proved to be reversible following a drug-free rehabilitation phase. Most importantly, we observed, that i.p. administration of PFK-158 led to elevated concentration levels of the immune-activating cytokine IFN-ɣ, while the concentration of immune-suppressing anti-inflammatory cytokines IL-4 and IL-6 declined in vivo. Moreover, immunohistochemical examination of the tumor tissue samples revealed an increase in tumor-infiltrating CD8+ lymphocytes under PFK-158 treatment. Conclusion: Our research demonstrates that direct PFKFB3 inhibition not only impairs tumor growth via metabolic restrain in OC but also leads to tipping the scales towards a more effective anti-tumor immune response.
glycolysis, immune modulation, PFKFB3, PFK-158
Jeske, Assja
2023
English
Universitätsbibliothek der Ludwig-Maximilians-Universität München
Jeske, Assja (2023): The immune-modulating effects of PFKFB3 inhibition in a syngeneic ovarian cancer model. Dissertation, LMU München: Faculty of Medicine
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Abstract

Background: Despite significant advances in surgery and chemotherapy, ovarian cancer remains the leading cause of death among gynecological malignancies. In an effort to establish new therapies, the focus has shifted toward restricting cancer metabolism. A key regulatory enzyme, PFKFB3, is overexpressed in OC and plays an important role in promoting tumor cell growth. Targeting glycolysis via selective PFKFB3 inhibition has shown promising results in pre-clinical studies. Nevertheless, its effects on the hosts` ability to initiate a potent anti-tumor immune response remain unknown. In this study, we describe the effects of PFK-158, a novel selective molecule inhibitor of PFKFB3, on the immune profile of mice using a syngeneic ovarian cancer model. Methods: We investigated the anti-cancer activity and immune-modulating effects of PFK-158 treatment in vitro, ex vivo, and in vivo. The focus of this study has been the adaptive immune system and more specifically, the T cell-mediated immune response, being the most relevant prognostic factor in OC survival. Proliferation and metabolomic analysis were performed on serous ovarian cancer mimicking STOSE cells as well as murine T cells purified from splenic tissue. T cell secretory function was assessed by flow cytometry. Lastly, a comparative analysis of tumor burden and immunologic parameters in plasma, spleens, and ascitic fluid was performed in the control and treatment groups. Results: Our study showed that PFKFB3 inhibition decreased the proliferation of malignant cells by metabolic restriction in vitro and resulted in suppressed tumor growth in vivo. PFK-158 also inhibited T cell viability, proliferation, and function as measured by cytokine release ex vivo. However, the loss of function proved to be reversible following a drug-free rehabilitation phase. Most importantly, we observed, that i.p. administration of PFK-158 led to elevated concentration levels of the immune-activating cytokine IFN-ɣ, while the concentration of immune-suppressing anti-inflammatory cytokines IL-4 and IL-6 declined in vivo. Moreover, immunohistochemical examination of the tumor tissue samples revealed an increase in tumor-infiltrating CD8+ lymphocytes under PFK-158 treatment. Conclusion: Our research demonstrates that direct PFKFB3 inhibition not only impairs tumor growth via metabolic restrain in OC but also leads to tipping the scales towards a more effective anti-tumor immune response.