Background
Lung cancer still accounts for the most cancer-related deaths worldwide. Although immune checkpoint blockade therapy is now the frontline therapy for lung adenocarcinomas with non-targetable oncogenic KRAS mutations, patients still have poor prognosis, which highlights the need to improve immunotherapy-based treatment strategies. Recently we identified that the systemic downregulation of the anti-inflammatory protein A20, induces a tumor-suppressive microenvironment in mouse models of lung cancer. This indicates A20 as a potential target for immune modulation to enhance the efficacy of immune-based therapies.
Materials and Methods
Using mouse models of KRAS-driven lung tumorigenesis, we evaluated the response of the tumor immune microenvironment to partial A20 knockdown in the stroma. In vitro and in vivo evaluations of A20 heterozygous and wild type CD8+ T cells were conducted using flow cytometry, RT-qPCR, tumor size measurement, survival assay and RNA sequencing.
Results
We discovered that systemic reduction in expression of the immune-modulatory enzyme A20, as seen in A20 heterozygous mice, induced modifications in the tumor microenvironment. This led to the formation of an anti-tumorigenic milieu, facilitating heightened infiltration of CD4+ and CD8+ T lymphocytes, as well as dendritic cells. In our in vitro experiments, we discovered that downregulation of A20 in CD8+ T cells in an increased capacity for proliferation and demonstrated anti-tumor activity in in vitro killing assays compared to wild-type CD8+ T cells. Moreover, adoptive transfer of antigen-specific CD8+ T cells led to a more pronounced reduction in tumor cell growth in A20 heterozygous recipients compared to wild-type recipients. This enhanced effectiveness of T cell transfer can be attributed to the potent anti-tumorigenic microenvironment present in the A20 heterozygous mice.
Conclusions
Our preliminary results demonstrated that systemic downregulation of the anti-inflammatory protein A20 in immune cells of the stroma, enhances the anti-tumor capability of CD8+ T cells and impedes tumor growth in mice. Additional experiments are required to investigate whether a combination therapy approach based on controlled A20 knockdown in immune cells and immune checkpoint blockade is efficacious in limiting tumor growth in KRAS driven lung adenocarcinoma.
M. Homolya: None. M. Machtinger: None. S. Lim: None. Z. Krevh: None. E. Casanova: None. H.P. Moll: None.