Year: 2025
Type: conference-abstract
Abstract: Background Lung cancer is the second most commonly diagnosed cancer worldwide and remains the leading cause of cancer-related mortality. Although immune checkpoint blockade therapy has become the first-line treatment for KRAS-mutated lung adenocarcinoma, resistance remains a significant challenge, highlighting the need for improved immunotherapy strategies. The anti-inflammatory protein A20, a key negative regulator of the NF-κB pathway, has emerged as a promising candidate for modulating the tumor microenvironment. Consequently, this study investigates how A20 modulation reshapes the tumor microenvironment, with the ultimate goal of enhancing the efficacy of immune-based therapies in KRAS-driven lung adenocarcinoma. Materials and Methods We used KRAS-driven lung adenocarcinoma mouse models to study how partial systemic downregulation of A20 affects the tumor immune microenvironment and immune response. Through adoptive transfer of A20 wild-type and A20-heterozygous antigen-specific T cells and by using A20 wild-type and A20 heterozygous recipients, we assessed their impact on cell therapy effectiveness. Ex vivo, we further analyzed how A20 downregulation influences CD8+ T cell cytotoxic activity and proliferation. Results Our study revealed that systemic reduction of A20, as observed in A20-heterozygous mice, induces an anti-tumorigenic tumor microenvironment. This microenvironment is characterized by enhanced infiltration of CD4+ and CD8+ T lymphocytes, as well as dendritic cells, in lung tumor-bearing mice. Ex vivo experiments showed that A20 downregulation in CD8+ T cells increases their proliferation and anti-tumor activity in cytotoxicity assays. Additionally, adoptive transfer of antigen-specific A20-heterozygous CD8+ T cells led to greater tumor growth reduction in Rag2-/- recipient mice. Similarly, tumor-bearing A20-heterozygous recipients showed improved tumor control after receiving wild-type CD8+ T cells compared to wild-type recipients. These findings indicate that A20 downregulation enhances the anti-tumor activity of CD8+ T cells. Furthermore, systemic A20 reduction amplifies the efficacy of adoptive cell transfer by fostering a strongly anti-tumorigenic microenvironment in A20-heterozygous mice. Conclusions This study serves as proof of principle, demonstrating that systemic downregulation of A20 can shape a tumor-suppressive microenvironment and enhance CD8+ T cell effector functions, leading to better tumor control in KRAS-driven lung adenocarcinoma. These findings highlight the translational potential of A20 as a promising therapeutic target to optimize cellular and immunotherapies. By selectively modulating A20 expression in immune cells, this approach could significantly boost anti-tumor immunity. Moreover, combining controlled A20 knockdown with immune checkpoint blockade holds great promise for improving treatment efficacy. This work lays the foundation for further exploration of A20-targeted strategies in cancer therapy. M. Homolya: None. M. Schwab: None. M. Machtinger: None. E. Casanova: None. H.P. Moll: None.
Source: Poster presentations
Authors: M Homolya, M Schwab, M Machtinger, E Casanova, HP Moll
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W4408827949