Tumor Microenvironment Acidification and its Impacts on Tumor Suppression, Proliferation, and Immune Function
Raj Patel
Background: Cancer impacts millions of people each year around the world. In the United States alone, it was projected that there would be over 1,900,000 new cases of cancer and over 600,000 cancer-related deaths in 20221. It is becoming increasingly important to understand the various intricacies present in cancer pathology to create newer therapeutic targets to better treat this disease. One of the few areas that is being heavily researched is the highly complex tumor microenvironment (TME). The TME is a collection of tumor cells, immune cells, mesenchymal stromal cells (MSCs), blood vessels, and the extracellular matrix (ECM). The TME plays a critical role in the development and progression of cancerous growth by modulating immune function, metabolic needs, and most interestingly pH2. Acidification of the surrounding environment is primarily due to what we know as the Warburg effect. Cancer cells will utilize glycolytic pathways over oxidative pathways to produce ATP needed for rapid proliferation under aerobic conditions. A byproduct of this rapid glucose turnover is the excessive production of lactate, the significant cause of TME acidification. This acidification promotes angiogenesis and immunosuppression, making it more difficult to treat the cancer. 3
Objective: To understand the primary mechanism of TME acidification and to learn how acidification alters immune function in colorectal liver metastasis and melanomas.
Search Methods: An online search in the PubMed and the Frontiers in Oncology & Microbiology databases using the keywords: “tumor microenvironment”, “Warburg effect”, “Cancer acidification”, “acidification”, “Vacuolar ATPase”.
Results: When observing lactate-mediated TME acidification specifically in colorectal liver metastasis (CRLM), liver-resident natural killer cells (CD56bright NK) demonstrated diminished survivability due to acidification driving an increase in late apoptotic signals, mitochondrial ROS production, and by decreasing the rate of ATP generation. Even when cellular lactate transporters, SLC16A1 and SLC16A3, were inhibited, the generation of mitochondrial ROS was not decreased. This demonstrated that the inhibitory effects of lactic acid on the CD56bright NK cells were independent of their transport into the cells and more likely due to the lactate-mediated acidification of the TME4. On the other hand, TME acidification in melanomas leads to the polarization of macrophages to tumor-associated macrophages that support tumor growth via the increased expression of inducible cAMP early repressor protein (ICER). In melanoma cells, the expression of genes involved in organic acid generation positively correlated with the expression of ICER in macrophages5. Mice inoculated with melanoma cells with ICER knockouts (KO) were able to mount a robust anit-melanoma immune response leading to the elimination of the tumor. Tumor-associated macrophages (TAMs) in melanomas demonstrate a higher expression of ICER with its concentration increasing in areas of stronger acidification. Under acidotic conditions, even bone marrow-derived macrophages (BMDM) expressed similar levels of ICER to that of melanomic TAMs5. In melanomas, certain GPCR-encoding genes were upregulated, specifically Gpr65 and Gpr132. In BMDMs with either a Gpr65 KO or with direct antagonism of Gpr132, expression of ICER was reduced5. In the absence of ICER, TAMs were observed expressing higher levels of nitric oxide synthase and TNF which demonstrated a pro-inflammatory phenotype5.
Conclusion: A primary component of tumorigenicity revolves around the acidification of the TME. Acidification impairs immune function differently in various cancers. In CRLM, it drives CD56bright NK cells towards inefficiency and premature apoptosis. Conversely, in melanomas, TME acidification manipulates the polarization of macrophages to facilitate a pro-tumor environment. However, understanding the mechanisms tumors utilize to acidify the TME and how they exploit this property to enhance their immunoevasive capabilities can play a critical role in developing the next line of therapeutics that can improve treatment efficacy and ultimately health outcomes.
Works Cited:
1.Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2022. CA Cancer J Clin. Jan 2022;72(1):7-33. doi:10.3322/caac.21708
2.Anderson NM, Simon MC. The tumor microenvironment. Curr Biol. Aug 17 2020;30(16):R921-r925. doi:10.1016/j.cub.2020.06.081
3.de la Cruz-López KG, Castro-Muñoz LJ, Reyes-Hernández DO, García-Carrancá A, Manzo-Merino J. Lactate in the Regulation of Tumor Microenvironment and Therapeutic Approaches. Front Oncol. 2019;9:1143. doi:10.3389/fonc.2019.01143
4.Harmon C, Robinson MW, Hand F, et al. Lactate-Mediated Acidification of Tumor Microenvironment Induces Apoptosis of Liver-Resident NK Cells in Colorectal Liver Metastasis. Cancer Immunol Res. Feb 2019;7(2):335-346. doi:10.1158/2326-6066.Cir-18-0481
5.Bohn T, Rapp S, Luther N, et al. Tumor immunoevasion via acidosis-dependent induction of regulatory tumor-associated macrophages. Nat Immunol. Dec 2018;19(12):1319-1329. doi:10.1038/s41590-018-0226-8