Abstract 7460: Characterizing the role of PCBP1 in the activation of the cGAS-STING/type I Interferon axis to promote anti-tumor immunity

Abstract

Abstract The emergence of immunotherapies has encouraged the need to better understand the molecular mechanisms that modulate the tumor immune microenvironment to kill cancer cells as well as the strategies used by cancer cells to evade the immune system. In several cancer types, the Poly(rC) Binding Protein 1 (PCBP1) has shown to have tumor suppressive effects, however its function in regulating the tumor immune environment remains unclear. To investigate this in the context of breast cancer, we established a CRISPR-Cas9-medited knock-out of PCBP1 in a Py8119 murine breast cancer cell line. PCBP1−/− cells revealed a decrease in the activation of the cGAS-STING pathway and is associated with lower levels of type I interferons (IFNs) and Interferon Stimulated Genes’ (ISGs) expression. The cGAS-STING pathway plays an important role in innate immunity as it fights pathogenic infections and tumorigenesis through the production of type I IFN and ISGs. It also promotes the priming and infiltration of T cells at the tumor site to fight cancer cells. Our results suggested that PCBP1 is acting on the activation of the cGAS-STING pathway and could further modulate the tumor immune microenvironment. We then confirmed our results in vivo by establishing a tumorigenic C57BL/6 PyMT transgenic mouse model with conditional knockout for PCBP1 in mammary cells. Our data demonstrate that PCBP1−/− PyMT mice have higher tumor burdens compared to PCBP1+/+ PyMT mice and also show a decreased ISGs’ signature by RNA-sequencing, qPCR and western blot, as previously observed in vitro in the Py8119 PCBP1−/− cell line. Additional single nuclei RNA-sequencing analyses confirmed that this downregulation of ISGs is observed in mammary cancer cells where PCBP1 is knocked-out. Strikingly, IHC and flow cytometry analyses of PCBP1−/− tumors isolated from these mice also revealed a decrease in CD8+ T-cells. Therefore, PCBP1 silencing may promote tumor growth by impairing the activation of the cGAS-STING/IFN-I/ISGs axis, which may contribute to the decrease in CD8+ T-cells’ infiltration at the tumor site. Additionally, we are further investigating the molecular mechanisms mediated by PCBP1 that trigger this activation of the cGAS-STING pathway. Citation Format: Cécile Fréreux, Paramita Chakraborty, Annamarie C. Dalton, Breege V. Howley, Bryan Granger, Joseph A. Karam, Silvia G. Vaena, Martin J. Romeo, Philip H. Howe. Characterizing the role of PCBP1 in the activation of the cGAS-STING/type I Interferon axis to promote anti-tumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7460.