J Exp Med: Accident! Inhibiting tumor resistance genes weakens the anti-cancer immune response and is not the best way to fight cancer!

!--webeditor: page title-- May 4, 2020 / -- For most cancer patients, the unfortunate reality is that they will face resistance to one or more chemotherapy drugs that are used to eliminate their disease.
the more serious problem is that once a patient's tumor becomes resistant to one type of chemotherapy, it is also more likely to develop resistance to other chemotherapy, a problem long known as multidrrodo resistance.
once the patient reaches this level, the prognostication is often poor.
past 35 years, scientists have tried to understand and stop multidring resistance in cancer through experimental drugs.
interestingly, new data from the Scripps Institute in Florida suggests that this may not be the best approach.
team found that inhibiting key genes associated with cancer resistance can have unintended side effects on a special immune system cell called CD8 plus cytotoxic T lymphocytes (CTLs).
Because CTLs are "killer" T-cells that play a vital role in fighting viral and bacterial infections and tumors, this may weaken the anti-cancer immune response and potentially increase susceptible to infection.
photo source: J Exp Med (2020) 217 (5) e20191388 Research published recently in The Journal of Test Medicine, entitled "The Journal of Health and function of the MDR1 transporter in Cytoxic T lymphocytes", the study shows that Repeated failures of multidruped resistance gene 1 (MDR1) inhibitors in human cancer trials may be due to the basic function of a previously undiscovered CTLs MDR1 gene.
several genes are now thought to be the cause of cancer multidring resistance, but the first and most prominent one is MDR1.
more than three decades ago, its discovery sparked a race to develop drugs that inhibit MDR1 expression.
but these MDR1 inhibitors have been disappointing in clinical trials.
reasons behind these failures remain a mystery.
: "MDR1 acts as an external pump for chemotherapy drugs in tumor cells, although its physiological function remains a mystery.
"using new genetic methods to visualize and evaluate the expression of MDR1 in mouse cells, the team found that CTLs were unique in terms of constant and high levels of MDR1 expression.
In addition, blocking the expression of MDR1 in CTL, or using inhibitors previously tested in human cancer trials to block its function, can trigger a chain reaction of CTL dysfunction that ultimately prevents these cells from being resistant to viral or bacterial infections.
"Using the recently developed MDR1-Knocking Report gene allegant gene (Abcb1aAME) system, we found that MDR1 is expressed in cytotoxic lymphocytes in hematocytes, including CTLs and natural killer cells, and regulated by Runt-related transcription factors (Runx)," the authors wrote.
MDR1 is essential for the development of childish CD8-plus T cells, but it is necessary for the normal accumulation of CTLS after acute viral infection and the protective function of memory CTLs after bacterial infection in cells.
MDR1 functions early after the in viability of childish CD8-T cells, suppressing oxidative stress, enhancing survivability, and protecting the mitochondrial function of the newborn CTLs.
"given that these cells are also necessary to kill most cancerous tumors, blocking MDR1 with existing inhibitors may also weaken the natural immune response to cancer."
"With the help of our collaborators at New York University Medical Center, we looked at mouse immune cells from five major lymphatic and non-lymphatic tissues: bone marrow, thymus, spleen, lungs, and small intestine," explained Dr. Mark Sundrud, associate professor of immunology and microbiology at the Scripps Research Center and a senior researcher.
" it is clear that the key cell types to fight infection and cancer are those most sensitive to blocking MDR1 function.
decades, it has been known that CTLs and "natural killer" cells express high levels of the MDR1 gene.
, however, because MDR1 has historically only been thought of as producing multidrring resistance in cancer cells, few researchers have thought about asking what role MDR1 played in a normal immune response.
Sundrud said those who found confusing and often contradictory results were most likely due to the use of nonse specific animal model systems.
Sundrud and his colleagues, convinced that MDR1 may affect the natural immune response, tried to design more specific mouse models to look directly at the expression of MDR1 in the body and functionally describe its characteristics.
other experiments have shown that blocking the function of MDR1 hinders CTL's early response to infection -- when these cells multiply rapidly to the amount needed to kill all virus and bacterial invaders.
consistent with this result, MDR1 inhibition also affects long-term immunity to previously detected and eradicated infections.
also affects the cell's energy cell, the mitochondrial.
think MDR1 plays a special role in helping mitochondrials provide energy to growing cells," Sundrud said.
, if you take this away, these cells can't support the metabolic needs of cell division, and they end up dying, and that makes sense."
" Photo Source: JEM On the one hand, the study raises questions about the safety and practicality of using systemic MDR1 inhibitors as cancer treatments.
, the study sheds light on important new mechanisms that determine how the immune system fights infection and develops long-term memory.
Sundrud said: "These insights are all the more relevant today, given all the issues and concerns associated with immunization against the pandemic coronavirus that causes COVID-19.
team now hopes to use this new knowledge to final determine the uniform function of MDR1 in all cells, whether in CTL, which responds to infection, or cancer cells that are trying to respond to chemotherapy drugs.
!--/ewebeditor:page--!--ewebeditor:page-title" -- in the short term, Scripps researchers plan to explore new ways to redesign existing MDR1 inhibitors specifically for cancer cells.
, you can prevent cancer cells from developing multidrrupable resistance without affecting immune cells," Sundrud concluded.
" () Reference: Adding Cancer Drug Resistance Gene May Not Best Approach Mei Lan Chen et al. Ysystod expression y function of the MDR1 transporter in cytoxic T lymphocytes. J Exp Med (2020) 217 (5): e20191388. https://doi.org/10.1084/jem.20191388!--/ewebeditor:page--.