Tumor-on-a-chip as a model to evaluate innate immune response after treatment of prostate cancer cells with p53 gene therapy and cabazitaxel

• Grant number: 23/12337-1
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate (Direct)
• Start date: February 01, 2024
• End date: January 31, 2025
• Field of knowledge: Biological Sciences - Immunology - Cellular Immunology
• Principal Investigator: Bryan Eric Strauss
• Grantee: Nadine Gimenez de Assis
• Supervisor: Wouter Verdurmen
• Host Institution: Instituto do Câncer do Estado de São Paulo Octavio Frias de Oliveira (ICESP). Coordenadoria de Serviços de Saúde (CSS). Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil
• Institution abroad: Radboud University Medical Center (Radboudumc), Netherlands
• Associated to the scholarship: 19/03055-7 - Induction of immunogenic cell death by associating gene transfer and chemotherapy in human prostate carcinoma cells, BP.DD

Abstract

Prostate cancer (PC) is a leading cause of death in male cancer patients worldwide and its low immunogenicity and high tumor heterogeneity make it less responsive to the immunotherapy options currently available. However, alterations in tumor suppressor genes such as p53 are clinically relevant and may serve as a target for the development of new therapeutic strategies for these patients. Our group has previously shown that a non-replicating adenoviral vector encoding p53 can eradicate PC in mice when combined with low doses of cabazitaxel (CBZ), increasing survival and reducing the toxicity of the chemotherapeutic agent. Nonetheless, these studies lack evaluation of the impact that this combined approach may have on the immune cells present in the tumor microenvironment (TME). As immunological studies advance, it is clear now that effector immune responses are needed for long-lasting responses in patients harboring metastatic tumors. Our recent in vitro results have shown pro-immunogenic signals as a result of p53 gene transfer and their enhancement when treatment included CBZ. The downregulation of CD47, for example, suggests involvement of innate immune cell responses, especially macrophages. Hence, we propose a deeper investigation of how our p53 gene therapy and CBZ combination approach can modulate macrophage responses. For this, we will use a 3D, tumoron-a-chip microfluidic model that better represents the structure and interactions of the TME as compared to standard monolayer cultures. Additional treatment modalities and components of the TME will be explored. (AU)