Cancer drug resistance study raises immune red flags

April 17, 2020

JUPITER, Fla.--April 17,2020--Sooner or later, most cancer patients develop resistance to the very chemotherapy drugs designed to kill their cancer, forcing oncologists to seek alternatives. Even more problematic, once a patient's tumor is resistant to one type of chemotherapy, it is much more likely to be resistant to other chemotherapies as well, a conundrum long known as multidrug resistance. Once patients reach this point, the prognosis is often poor, and for the last 35 years scientists have attempted to understand and block multidrug resistance in cancer by using experimental medicines.

A new study from scientists at Scripps Research in Florida raises red flags about this strategy. Inhibiting the key gene involved in cancer drug resistance has unintended side effects on specialized immune system cells called CD8+ cytotoxic T lymphocytes (CTLs), the team found. This could dull anti-cancer immune responses, and potentially increase vulnerability to infection, since CTLs are "killer" T cells, essential in the fight against both viral and bacterial infections and tumors, says lead author Mark Sundrud, PhD, associate professor of Immunology and Microbiology at Scripps Research.

Several genes are now recognized for contributing to multidrug resistance in cancer, but the first and most prominent of these is called multidrug resistance-1 (MDR1). Its discovery more than three decades ago set off a race to develop drugs that would inhibit expression of MDR1. But those MDR1 inhibitor drugs have consistently disappointed in clinical trials. The reasons behind these failures have remained enigmatic.

In a new study published Thursday in the Journal of Experimental Medicine, Sundrud and colleagues including Scripps Research immunologist Matthew Pipkin, PhD, suggest that the repeated failure of MDR1 inhibitors in human cancer trials may be due to a previously unrecognized--and essential--function of the MDR1 gene in CD8+ cytotoxic T lymphocytes.

Using new genetic approaches to visualize and functionally assess MDR1 expression in mouse cells, the team found that CTLs were unique in their constant and high-level expression of MDR1. In addition, preventing MDR1 expression in CTLs, or blocking its function using inhibitors previously tested in human cancer trials, sets off a chain reaction of CTL dysfunction, ultimately disabling these cells from fighting off viral or bacterial infections.

Considering that these cells are also necessary for warding off most cancerous tumors, blocking MDR1 with existing inhibitors could also cripple natural immune responses to cancers, Sundrud says.

"With the help of our collaborators at New York University Medical Center, we looked at mouse immune cells from five major lymphoid and nonlymphoid tissues: bone marrow, thymus, spleen, lung, and small intestine," Sundrud says. "It became clear that the types of cells that are key to fighting infections and cancers, are among those most sensitive to blocking MDR1 function."

It has been known for decades that CTLs, as well as "natural killer" cells, a type of white blood cell, express high levels of the MDR1 gene. But because MDR1 has historically been viewed only through the lens of creating multidrug resistance in cancer cells, few researchers thought to ask what MDR1 does during normal immune responses; those that did found confusing and often contradictory results, Sundrud says, likely due to the use of non-specific animal model systems.

Convinced that MDR1 might impact natural immune responses, Sundrud and colleagues sought to devise more specific mouse models to directly visualize and functionally characterize MDR1 expression in vivo. Additional experiments revealed that blocking MDR1 function hampered the earliest stages of the CTL response to infections, when these cells multiply rapidly to reach the numbers needed to kill all viral and bacterial invaders. In line with this result, MDR1 inhibition also affected long-lived immunity to infections that have been previously seen and eradicated. It also affected the cells' energy organelles, called mitochondria.

"We think that MDR1 plays a special role in helping mitochondria provide energy to growing cells" Sundrud says. "So, if you take this away, it makes sense that these cells can't support the metabolic demand of cell division, and that they ultimately die."

On one hand, Sundrud says, the research raises questions about the safety and utility of using systemic MDR1 inhibitors as cancer therapies. At the same time, the work reveals important new mechanisms that determine how the immune system fights off infections and develops long-lived memory.

"These insights become all the more pertinent today, given all the questions and concerns related to immunity against the pandemic coronavirus that causes COVID-19," Sundrud says.

The team is now looking to use this new knowledge to finally nail down a unifying function of MDR1 in all cells, whether it is in CTLs responding to infections, or cancer cells trying to deal with chemotherapeutic agents.

In the shorter term, Sundrud and colleagues plan to explore new approaches to re-design existing MDR1 inhibitors to specifically target only cancer cells.

"This way you might be able to prevent multidrug resistance in cancer cells, without affecting the immune cells that are trying to fight off the tumor", Sundrud says.
Additional authors of "Physiological expression and function of the MDR1 transporter in cytotoxic T lymphocytes," are co-author Sergei B. Koralov of New York University Medical Center; first authors Mei Lan Chen of Scripps Research and Amy Sun of New York University Medical Center; as well as Wei Cao, Amber Eliason, Kayla M. Mendez, Adam J. Getzler, Shanel Tsuda, Huitian Diao, Clever Mukori, Nelson E. Bruno, Sang Yong Kim, and Matthew E. Pipkin all of Scripps Research.

Scripps Research Institute

Related Cancer Articles from Brightsurf:

New blood cancer treatment works by selectively interfering with cancer cell signalling
University of Alberta scientists have identified the mechanism of action behind a new type of precision cancer drug for blood cancers that is set for human trials, according to research published in Nature Communications.

UCI researchers uncover cancer cell vulnerabilities; may lead to better cancer therapies
A new University of California, Irvine-led study reveals a protein responsible for genetic changes resulting in a variety of cancers, may also be the key to more effective, targeted cancer therapy.

Breast cancer treatment costs highest among young women with metastic cancer
In a fight for their lives, young women, age 18-44, spend double the amount of older women to survive metastatic breast cancer, according to a large statewide study by the University of North Carolina at Chapel Hill.

Cancer mortality continues steady decline, driven by progress against lung cancer
The cancer death rate declined by 29% from 1991 to 2017, including a 2.2% drop from 2016 to 2017, the largest single-year drop in cancer mortality ever reported.

Stress in cervical cancer patients associated with higher risk of cancer-specific mortality
Psychological stress was associated with a higher risk of cancer-specific mortality in women diagnosed with cervical cancer.

Cancer-sniffing dogs 97% accurate in identifying lung cancer, according to study in JAOA
The next step will be to further fractionate the samples based on chemical and physical properties, presenting them back to the dogs until the specific biomarkers for each cancer are identified.

Moffitt Cancer Center researchers identify one way T cell function may fail in cancer
Moffitt Cancer Center researchers have discovered a mechanism by which one type of immune cell, CD8+ T cells, can become dysfunctional, impeding its ability to seek and kill cancer cells.

More cancer survivors, fewer cancer specialists point to challenge in meeting care needs
An aging population, a growing number of cancer survivors, and a projected shortage of cancer care providers will result in a challenge in delivering the care for cancer survivors in the United States if systemic changes are not made.

New cancer vaccine platform a potential tool for efficacious targeted cancer therapy
Researchers at the University of Helsinki have discovered a solution in the form of a cancer vaccine platform for improving the efficacy of oncolytic viruses used in cancer treatment.

American Cancer Society outlines blueprint for cancer control in the 21st century
The American Cancer Society is outlining its vision for cancer control in the decades ahead in a series of articles that forms the basis of a national cancer control plan.

Read More: Cancer News and Cancer Current Events is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to