Abstract A22: Cervical cancer immunomodulation through stat3 and p65 NFκb: Effects beyond the tumor microenvironment

Abstract

Abstract Chronic signaling by molecules generated in the tumor microenvironment has local and systemic effects on the immune system. We have previously shown that cervical cancer cells express cytokines as IL-6 and G-CSF, among other factors. These cytokines have been associated with cancer progression in several types of cancer, either by promoting chronic inflammation and/or tolerance. Trying to better understand how cells from the immune system and tumor integrate signals generated by the tumor microenvironment, we have investigated the activation status of signaling pathways involved in cell proliferation and survival, inflammation and immune responses. We observed a cohort of cervical cancer patients, all of whom had cervical biopsies positive for high oncogenic risk human papillomavirus (HPV). In the cervical cancer biopsies, we found constitutive expression of phosphorylated STAT3, Akt, p65 NFκB and CREB, in both the tumor and leukocyte compartments. In the peripheral blood, however, we found constitutive expression of phosphorylated STAT3 and Akt, but significantly lower expression of phosphorylated p65 NFκB than in controls. Data previously published by our laboratory using a HPV16 experimental model showed high constitutive expression of phospho-STAT3 and low negative expression of phospho-p65 NFκB in splenocytes of tumor-bearing mice compared to controls. Given the data from our patients, we hypothesized that the high STAT3 expression and low NFκB expression could have a correlation, with a biologic effect on tumor-bearing subjects. Again, using an HPV16 experimental model, we neutralized IL-6 and G-CSF expression or pharmacologically inhibited STAT3 with the NSC74859 compound. In both cases, we observed significant reduction in tumor growth, decrease in phospho-STAT3 expression (when using the neutralizing antibodies), and importantly, significant increase in phospho-p65 NFκB expression. We also observed a significant increase in T-cell infiltration in tumors from treated animals and increase in antigen-specific T-cell proliferation. Our data indicate that cytokines that signal chronically through STAT3 can inhibit antitumor immune responses through NFκB inhibition. We also suggest that inhibition of STAT3 may be used as therapeutic tool against cervical cancer and other HPV-associated cancers. Financial support: FAPESP 2014/19326-6; 2008/57889-1; CNPq 573799/2008-3. Citation Format: Renata Ariza Marques Rossetti, Gretel Rodriguez Rodriguez, Ildelfonso Alves Da Silva, Jr. Jesus De Paula Carvalho, Maria Beatriz Sartor De Faria Rosa, Luisa Lina Villa, Ana Paula Lepique. Cervical cancer immunomodulation through stat3 and p65 NFκb: Effects beyond the tumor microenvironment [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr A22.