Gianpiero Paletta

Background: Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related mortality, with a five-year survival rate of only 10%¹. Due to its nonspecific symptoms, approximately 80% of PDAC diagnoses are made when the disease has already metastasized, making effective treatment challenging¹. Currently, surgical resection offers the best prognosis but is feasible for only 20% of patients. Chemotherapy, the secondary treatment option, shows limited efficacy¹. PDAC cells exhibit the Warburg effect, preferring glycolysis over oxidative phosphorylation, which increases lactic acid production². To manage this acidity, cancer cells either export protons or import bicarbonate, contributing to an acidic tumor microenvironment (TME)². This acidic TME promotes tumor aggression and immunosuppression, making it a promising target for therapeutic intervention^3-4. Solute carrier family 4 member 4 (Slc4a4), a predominant sodium-bicarbonate transporter in PDAC epithelial cells, emerges as a critical target. Inhibiting Slc4a4 could reverse the acidic TME’s effects and enhance therapeutic outcomes⁵.

Objective: In this narrative review, we explored the mechanisms of how targeting the Slc4a4 channel in pancreatic cancer cell lines, reverses the effects of the acidic TME.

Search Methods: An online search in the PubMed database was conducted from 2018-2023 using the following keywords: “pancreatic cancer”, “immunosuppression”, and “acidic tumor microenvironment”.

Results: In this study, single-cell RNA sequencing of epithelial cells from a cohort of 10 patients with naïve pancreatic ductal adenocarcinoma (PDAC) revealed that Slc4a4 was the most highly expressed bicarbonate channel⁵. Two murine PDAC cell lines, PANC02 and KPC, were engineered using the CRISPR-Cas9 system to include either a sgRNA targeting Slc4a4 or a non-targeting control sgRNA⁵. Targeting Slc4a4 resulted in reduced bicarbonate uptake and intracellular pH, alongside an increase in extracellular pH, both in vitro and in vivo in mouse models⁵. Furthermore, targeting Slc4a4 significantly reduced tumor weight and size in both subcutaneous and orthotopic models⁵. This intervention also led to decreased metastasis, evidenced by fewer nodules in the mesenteric, lung, and liver lymph nodes⁵. In mice bearing sgSlc4a4 pancreatic cancer cells, there was enhanced infiltration, activation, and an increased CD8⁺ T cell to T_reg ratio⁵. Additionally, these mice exhibited prolonged survival when treated with immune checkpoint blockade (ICB) therapy, including anti-PD1, anti-CTLA4, and combined therapies⁵.

Conclusion: Targeting the Slc4a4 channel in pancreatic cancer seems to inhibit the effects of the acidic TME. Slc4a4 in colorectal and prostatic cancer correlates with the increase in prognosis and inflammatory TME, making it a potential target in other cancers^6-7. Consideration of targeting the Slc4a4 in cancer could lead to promising therapeutic outcomes.

Work Cited:

1. Park W, Chawla A, O’Reilly EM. Pancreatic Cancer. JAMA. 2021;326(9):851-862. doi:https://doi.org/10.1001/jama.2021.13027
2. Boedtkjer E, Pedersen SF. The Acidic Tumor Microenvironment as a Driver of Cancer. Annual Review of Physiology. 2020;82(1):103-126. doi:https://doi.org/10.1146/annurev-physiol-021119-034627
3. Rao D, Stunnenberg JA, Lacroix R, et al. Acidity‐mediated induction of FoxP3⁺ regulatory T cells. European Journal of Immunology. 2023;53(6). doi:https://doi.org/10.1002/eji.202250258
4. Czaplinska D, Ialchina R, Andersen HB, et al. Crosstalk between tumor acidosis, p53 and extracellular matrix regulates pancreatic cancer aggressiveness. International Journal of Cancer. 2022;152(6):1210-1225. doi:https://doi.org/10.1002/ijc.34367
5. Cappellesso F, Orban MP, Shirgaonkar N, et al. Targeting the bicarbonate transporter SLC4A4 overcomes immunosuppression and immunotherapy resistance in pancreatic cancer. Nature Cancer. 2022;3(12):1464-1483. doi:https://doi.org/10.1038/s43018-022-00470-2
6. Rui S, Wang D, Huang Y, Xu J, Zhou H, Zhang H. Prognostic value of SLC4A4 and its correlation with the microsatellite instability in colorectal cancer. Frontiers in oncology. 2023;13. doi:https://doi.org/10.3389/fonc.2023.1179120
7. Liu Z, Wang Q, Zhai G, Ke S, Yu X, Guo J. SLC4A4 promotes prostate cancer progression in vivo and in vitro via AKT-mediated signalling pathway. Cancer Cell International. 2022;22(1). doi:https://doi.org/10.1186/s12935-022-02546-6