by University of Oklahoma

PDAC cells create a vitamin B6-defective microenvironment that inhibits NK-cell activation. A, PCA plot of RNA-seq results of NK cells cocultured with HPNE, T3M4, CFPAC1, and Capan2. B, GSEA of inflammatory response genes based on RNA-seq data from NK cells were cocultured with PDAC cells, HPNE, or K562. C, Heat map of the mRNA expression of genes related to NK-cell cytotoxicity. D and E, Flow cytometry analysis showing the expression of NKG2A and TIGIT in NK (CD3−, NK1.1+) cells from KPC1245 orthotopic tumors or healthy mice blood. F, Dead cell percentage of CFPAC1 after coculture with NK cells under different conditions. CM, cells were cocultured in a CFPAC1-conditioned medium. FM, cells were cocultured in fresh medium. G and H, Expression of IFNγ and CD107a in NK cells from different conditions in F. I, Dying cell percentage of K562 upon coculturing with NK cells from different conditions. FM-NK, cells were cocultured in a fresh medium. CM-NK, cells were cocultured in the CFPAC1 CM. CM >3 kDa-NK, cells were cocultured in basal NK-cell medium with >3 kDa macromolecular components from CFPAC1 CM. CM <3 kDa-NK, cells were cocultured in <3 kDa molecular components from CFPAC1 CM. J and K, The percentage of IFNγ- and CD107a-positive cells in NK cells form different conditions as in I after coculturing with K562 cells. L, Partial least squares discriminant analysis (PLS-DA) plot of metabolites in NK-cell after coculturing with different cells. M, Top affected metabolic pathways in NK cells when cocultured with PDAC cells [co-PDAC (co-Panc1, co-T3M4, and co-Capan2) vs. co-CTL (NK only and co-HPNE)]. N and O, Relative intracellular levels of pyridoxine and pyridoxal phosphate (PLP) in NK cells after coculturing with the indicated cells. P and Q, Pyridoxine and PLP levels in plasma and tumor interstitial fluid from healthy tumor-free mice and mice with KPC1245 tumors. R, Serum PLP level from patients with pancreatic cancer or gallbladder stone. S, Dead cell percentage of K562 and HPNE cells after coculturing with NK cells that were precultured in media with different VB6 (pyridoxine) levels. Data, mean ± SEM. Unpaired Student t test (two-tailed) was used for D, E, and R. One-way ANOVA with Tukey multiple comparisons test was used for F–K, N–Q, and S. *, P < 0.05; **, P < 0.01; ***, P < 0.001; ns, not significant. Credit: Cancer Discovery (2023). DOI: 10.1158/2159-8290.CD-23-0334

Vitamin B6 is beneficial in many ways, notably for its role in maintaining a strong immune system. However, when pancreatic cancer develops, its cells also need vitamin B6 to replicate. During the ensuing tug-of-war over a limited supply of vitamin B6, pancreatic cancer almost always emerges as the victor. A researcher at the University of Oklahoma College of Medicine is following a promising trail of clues in an effort to reverse that reality.

Kamiya Mehla, Ph.D., is an associate professor of oncology science at the OU College of Medicine and a researcher with the OU Health Stephenson Cancer Center. Her research seeks ways to invigorate the body's immune system against invaders like pancreatic cancer.

In a recent publication in the journal Cancer Discovery, Mehla details the role of vitamin B6 in healthy people and when pancreatic cancer is present. Vitamin B6, which can be found in a variety of foods like chicken, fish, and bananas, supports immune system cells, including natural killer (NK) cells, which are the first to respond to anything from cancer to a common cold.

However, in the presence of pancreatic cancer, NK cells are noticeably absent. That's because the cancer cells use up all the vitamin B6 that the NK cells need to do their job.

"Pancreatic cancer is very difficult to treat, and only 11% of people who are diagnosed survive for five years," Mehla said.

"It's important that researchers study pancreatic cancer from many different angles in order to develop new treatments. My laboratory is focused on the role of vitamin B6 because we know it boosts the immune system, but we need to understand more about how it affects cancer cells. We hope that our work opens new avenues for developing novel treatments for pancreatic cancer."

In her lab, Mehla found that giving more vitamin B6 still doesn't help the NK cells—the pancreatic cancer cells actually grew more when they could devour additional nutrients. She studied the actions that cancer cells take to deplete vitamin B6 and then devised ways to impede them.

She ultimately discovered a three-part strategy. Step one involves reducing the expression of a particular gene in order to block the pathway through which the cancer takes up vitamin B6. The second step is to supply more vitamin B6, and the third utilizes therapy to enhance the function of NK cells, like a tune-up for a car engine. When the strategy was tested in mice, it reduced the amount of pancreatic cancer cells.

"That was encouraging to discover," Mehla said, "and it is important to know because the immune system needs to be strong in order for other treatments, like chemotherapy, to be effective. Therapy will not work if the immune system is not able to do its part."

Mehla plans to continue her research in this area and to expand to related concerns. Because pancreatic cancer causes problems throughout the body in its attempt to gain more nutrients, she will study how a shortfall of vitamin B6 affects other organs, particularly the liver, when cancer cells are present. She is also studying whether a lack of vitamin B6 contributes to the onset of cachexia, a muscle-wasting condition that affects the majority of people with pancreatic cancer.

Because military members may be exposed to hazards like radiation and chemical toxins, they can face an increased risk of developing pancreatic cancer as they age. In addition to the cancer itself, cachexia diminishes the quality of life of many war veterans, Mehla said.

"When patients have such a dramatic loss of muscle, they are less likely to respond to treatment," she said. "Pancreatic cancer is a systemic disease. It's not just sitting there. It's trying to extract nutrients from multiple areas to help it survive. That's why it's important to take a broad look at how we can stimulate the immune system against tumors."

More information: Chunbo He et al, Vitamin B6 Competition in the Tumor Microenvironment Hampers Antitumor Functions of NK Cells, Cancer Discovery (2023). DOI: 10.1158/2159-8290.CD-23-0334

Journal information: Cancer Discovery 

Provided by University of Oklahoma