Abstract 183P
Background
In cancer, inflammation frequently coexists with hypoxia within the tumor microenvironment (TME), often creating an immunosuppressive environment. This hostile milieu is further exacerbated by acidosis, which collectively further hinders effective anti-tumor immune responses. Carbonic anhydrase IX (CAIX) is a well-established hypoxia marker that plays a key role in the pH regulation and adaptation of tumor cells to hypoxia resulting in tumor progression. The CAIX activity contributes to the formation of an acidic environment, which can suppress the function of cytotoxic T cells and other immune cells. While primarily induced by HIF1α under hypoxic conditions, CAIX expression can also be triggered in an inflammatory milieu by IL6 or the COX-2/PGE2 pathway. The goal of this study is to determine the role of CAIX in the regulation of inflammatory and anti-tumor immune responses.
Methods
CAIX+ and CAIX-silenced HT1080 cells were cultured in the presence of a conditioned (inflammatory) medium obtained from MUF spheroids (MUF-CM) under normoxic or hypoxic conditions. RNA samples were analyzed by Clariom, followed by unsupervised clustering. Gene Set Expression Analysis (GSEA) was used to analyze the gene expression. The relation between CAIX level and gene sets identified by GSEA was also analyzed in TCGA SARComa samples and pancreatic cancer (PC).
Results
We found that MUF-CM can upregulate CAIX expression in fibrosarcoma and PC cells even under normoxia. Our analysis revealed that suppression of CAIX leads to upregulation of hallmarks of IFN-α, IFN-γ, and inflammatory response. In silico analysis of TCGA SARC samples confirmed the relationship between lower CAIX expression and higher expression of IFN-α, IFN-γ and inflammation response gene sets, which predicted better overall survival. Moreover, the immune gene sets associated with immune activation and expression of HLA-antigens negatively correlated with CAIX.
Conclusions
Understanding the complex interplay between hypoxia, CAIX, and inflammation is crucial for developing effective cancer treatments. Given the central role of CAIX in this intricate relationship, targeting the function of this enzyme may represent a new opportunity to create a favorable milieu for anti-tumor immune response in the TME.
Legal entity responsible for the study
The authors.
Funding
The Slovak Research and Development Agency 20-0480.
Disclosure
All authors have declared no conflicts of interest.
Resources from the same session
226P - Profiling of gastric adenocarcinomas from EU and LATAM countries identifies distinct tumor immune subgroups and a central role of the tumor microbiome in shaping the immune microenvironment
Presenter: Manuel Cabeza Segura
Session: Poster Display session
Resources:
Abstract
228P - Modulating mitochondrial dynamics in TAMs to enhance anti-tumor immunity
Presenter: Pu-ste Liu
Session: Poster Display session
Resources:
Abstract
229P - Investigation of the effects of long-noncoding RNA NRAV on interferon response in melanoma
Presenter: Kadir Durmus
Session: Poster Display session
Resources:
Abstract
230P - Deciphering the mechanism of immunosuppressive activity of acetaminophen in the context of cancer immunotherapy
Presenter: Jeanne Lena
Session: Poster Display session
Resources:
Abstract
231P - The impact of calcitriol and tacalcitol on the Th17 lymphocytes in breast cancer
Presenter: Beata Filip-Psurska
Session: Poster Display session
Resources:
Abstract