Interaction between tumor and myeloid cells in Cervical Cancer patients, STAT3 role in immunomodulatory mechanisms

• Grant number: 20/11974-0
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: November 01, 2021
• End date: August 31, 2024
• Field of knowledge: Biological Sciences - Immunology
• Principal Investigator: Ana Paula Lepique
• Grantee: Lorraynne Letycia Prado da Cruz
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

The presence of immune cells in the tumor microenvironment is a well known feature. In some cancers, the microenvironment promotes progression tumor progression and immune responses suppression. Cells with this characteristics are myeloid derived suppressor cells, alternative macrophages, N2 neutrophils and others. Under this perspective, our laboratory has been investigating how myeloid cells can modulate T cell responses against HPV associated tumors, mainly cervical cancer. We have demonstrated that HPV transformed cells secrete IL-6 and G-CSF, factors that induce myeloid cell proliferation, and that patients with cervical cancer display an increase in circulating myeloid cells that seem to be low density neutrophils. These can directly promote tumor progression and angiogenesis and can trigger immune escape mechanisms. We work with the hypothesis that cells in the tumor microenvironment signal systemically to induce the accumulation of myeloid cells that are recruited to the tumor microenvironment forward feeding a cycle that leads to tolerance towards tumor antigens. The suppressive phenotype in myeloid cells depend on the activation of various signalling pathways. An important one seems to be JAK2/STAT3 that promotes expression of genes involved in cellular proliferation, survival, angiogenesis, inflammation and can be activated by IL-6, G-CSF and IL-10, among other factors. STAT3 chronic activation has been reported in several types of cancer, and is associated with tumor progression and immune suppression. For this reason, there are clinical trials testing STAT3 inhibition for cancer treatment. Our laboratory has recently shown that STAT3 inhibition results in tumor growth inhibition and increase in tumor antigen specific immune responses. Therefore, this project objectives are to compare myeloid cell populations from cervical cancer patients and clinically healthy donors in their capacity to activate or inhibit T cells. We will also treat myeloid and T cell co-cultures with STAT3 inhibitor to test if we can revert tolerogenic effects triggered by the myeloid population. Finally, using experimental models, we intend to identify tolerogenic mechanisms triggered by STAT3. We expect to be able to explain mechanisms by which STAT3 can systemically modulate immune responses against HPV associated cancers. (AU)