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2024-04-09| R&D

UT Southwestern Study Unveils Acidic Defense Mechanism of Cancer Cells

by Richard Chau
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In a recent study published in the journal Nature Biomedical Engineering, researchers from Dallas-based UT Southwestern Medical Center (UTSW) have uncovered a startling revelation about cancer cells – they release a significantly more concentrated level of acid to the tumor microenvironment than previously understood, forming what scientists describe as an “acid wall” that could keep attacking immune cells at bay. 

Under the leadership of Dr. Jinming Gao, Professor at the Harold C. Simmons Comprehensive Cancer Center and the Departments of Biomedical Engineering, Cell Biology, Otolaryngology – Head and Neck Surgery, and Pharmacology at UT Southwestern, the team’s findings shed light on a previously unrecognized aspect of tumor biology that could revolutionize cancer treatment strategies.

Related article: Implantable Oxygen-Eating Battery to Combat Cancer 

Unveiling an Acidic Tumor Microenvironment Against Antitumor Defense

For decades, scientists have recognized that tumors exhibit acidity, with a pH lower than that of healthy tissues. In humans, for example, the average pH of muscle at rest is about 7.4, but the value for malignant tumors is about 6.8. In spite of these prior discoveries, the extent and implications of this acidity have remained elusive until now. 

Prof. Gao’s team used pegsitacianine, a pH-sensitive micellar fluorescence agent that glows at a pH of 5.3, in their groundbreaking study as nanoparticle probes and imaged individual cells sampled from a variety of human and mouse cancer types such as lung cancer, breast cancer, melanoma, and glioblastoma. Upon administration, pegsitacianine accumulated in tumor tissue and this diagnostic dye fluoresced on one side of cancer cells but not the other, allowing the researchers to visualize a polarized acidity when comparing the interior of cancer cells and the extracellular environment due to heightened level of acid secretion beyond previous understanding. 

The team discovered that cancer cells excrete hydronium ions into a localized extracellular region at the tumor’s edge, leading to severely polarized acidity levels (pH <5.3). This phenomenon primarily arises from the secretion of lactic acid as evidenced by genetic knockout or inhibition of monocarboxylate transporters across various cancer cell types. 

An Acid Wall Against Antitumor Defense

In order to meet the substantial need of extra energy and materials for tumor growth and proliferation, cancer cells often reprogram their metabolism to enhance uptake and utilization of glucose. A higher rate of tumor glycolysis leads to excess lactic acid production, hence an increased extracellular acidification as mentioned.

This localized acidic microenvironment would form a protective barrier around the tumor, hindering infiltration and action of immune cells, particularly CD8+ cytotoxic T cells. What worsened the situation is that, in laboratory experiments, Prof. Gao’s team found that the exposure to severe acidity led to the demise of CD8+ T cells within hours, highlighting the formidable defense mechanism employed by cancer cells to evade immune surveillance. As a result, such an “acid wall” surrounding cancer cells could thwart immune attacks against them, compromising the body’s natural defense mechanism against various tumors. 

Exploiting Tumor Acidity To Develop Targeted Cancer Therapies 

The research team of UT Southwestern Medical Center envisions a paradigm shift in cancer treatment strategies based on their current findings. While previous approaches focused on exploiting tumor acidity for drug delivery, this study emphasizes the need to modulate the acidic microenvironment to enhance immune responses against cancer. According to Dr. Gao, one potential intervention involves the conversion of lactic acid into lactate, the conjugate base of lactic acid which the team had discovered its effect in enhancing the anti-cancer activity of immune cells, to promote immune attack against tumors. Additionally, given the heightened acidity levels revealed in this study, existing treatment approaches that leverage tumor acidity such as pH-sensitive drug carriers may require refinements to accommodate the situation.

With the aim of developing novel cancer therapies, Dr. Gao also suggested that a number of new research lines may emerge from this discovery, including studies into how cancer cells polarize their acid excretions, how they can withstand acidity levels that kill CD8+ T cells, and possible ways to inhibit such acid excretion to allow immune cells to deal a lethal blow to cancer cells more effectively.

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