17P - Breaking chemotherapy resistance in gastric adenocarcinoma: Immunogenic cell death induction by carbonic anhydrase IX targeting

Background

Gastric cancer (GC) is the fifth most common malignancy worldwide and the fourth leading cause of cancer-related death. When tumor resection is not possible, the perioperative chemotherapy (pCT) FLOT (Leucovorin, 5-Fluouracil, Docetaxel, and Oxaliplatin) represents the standard of care, at least in Europe, to enhance patients' overall survival. However, chemoresistance onset inevitably hampers treatment efficacy. Recently, we identified carbonic anhydrase IX (CAIX) as a promising target in GC patients, as its expression was correlated with resistance to the pCT regimen. Moreover, pre-clinical evidence showed that CAIX inhibition by the SLC-0111 compound - currently under phase Ib clinical trial for metastatic ductal pancreatic cancer – allowed boosted therapy response even in resistant GC cells. Our ongoing study aims to explore the mechanisms behind SLC-0111-induced cytotoxicity in GC and its ability to induce immunogenic cell death (ICD), thereby potentially triggering a broad anti-cancer immune response.

Methods

SLC-0111 and FLOT were administered as mono- or combined therapies to sensitive and FLOT-resistant GC cell lines. Cell death pathways and Damage Associated Molecular Patterns (DAMPs) expression by dying GC cells were assessed through flow cytometry (FC), ELISA, luminometry, and immunofluorescence. The phenotype of immune cells exposed to dying GC cells was evaluated in vitro by qPCR, FC, and ELISA techniques.

Results

Apoptotic and non-apoptotic immunogenic cell deaths such as alkaliptosis and ferroptosis were observed in GC subjected to the SLC-0111/FLOT treatment. Analysis of DAMPs showed increased cytoplasmic dsDNA levels, heightened Calreticulin and Annexin A1 exposure, and elevated release of High Mobility Group Box 1 and ATP by GC cells treated with SLC-0111/FLOT compared to the control group. Macrophage exposure to such a DAMP-enriched microenvironment resulted in M1 activation.

Conclusions

In summary, our findings indicate that the SLC-0111/FLOT combination therapy not only enhances treatment efficacy and restores sensitivity in resistant GC cells but also has the potential to induce ICD, which may stimulate an anti-cancer immune response to combat tumor progression.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

L. Papucci.

Funding

Italian Ministry of University and Research.

Disclosure

All authors have declared no conflicts of interest.