Nav: Home

PIM-2 protein kinase regulates T-cell activity differently than PIM-1 or PIM-3 isoform

June 15, 2018

The PIM-2 protein kinase negatively regulates T cell responses in transplantation and tumor immunity, while PIM-1 and PIM-3 are positive regulators, report Medical University of South Carolina (MUSC) investigators in an article published online on May 21, 2018 by The Journal of Clinical Investigation (JCI). Blocking PIM-2 in allogeneic bone marrow transplant (BMT) dramatically accelerated graft-versus-host disease (GVHD). In adoptive immunotherapy with autologous T cells, silencing PIM-2 on T cells produced robust tumor immunity, highlighting the importance of PIM-specific inhibition.

The PIM family of protein kinases contains three isoforms, PIM-1, PIM-2, and PIM-3, with very similar structures. Because they are known to affect cell survival and proliferation, the group is considered a promising therapeutic target in cancer. Additionally, pan-PIM inhibition (blocking all three isoforms) is often used for cancer therapy.

Because the isoforms are so similar, the assumption has been that they function in similar ways. However, in the JCI article, a team of MUSC researchers led by Xue-Zhong Yu, M.D., a professor in the Department of Microbiology and Immunology and SmartState Endowed Chair in Cancer Stem Cell Biology and Therapy at Hollings Cancer Center, showed that PIM-2 kinase has unique activity in regulating T cells that is in opposition to PIM-1 and PIM-3.

"This kinase family has been studied quite extensively in cancer biology. We know that tumors activate-or turn on--these kinases to survive better because all three isoforms help protect cancer cells from death by making them resistant to chemotherapy. That's why quite a few companies have developed pan-PIM inhibitors for cancer therapy," explains Yu.

While most research has focused on the role of PIM kinases in cancer biology, little is known about how they influence primary T cells and the immune response. Yu and his team set out to try to understand how these kinases regulate T cell responses in BMT and solid tumors.

Allogeneic BMT is an essential treatment for blood cancers such as leukemia, because, even after chemotherapy and radiation, a small number of cancer cells can remain in the bloodstream, allowing the malignancy to recur. Replacing a patient's bone marrow is the best way to prevent this, but an ideal, biologically matched donor is often not available. The less well-matched the donor, the higher the risk for developing GVHD, in which donor cells trigger an immune response that attacks the patient's normal tissues, causing high morbidity and mortality. Researchers have long sought ways to improve BMT success by reducing GVHD incidence while preserving the anti-tumor response of donor cells.

Yu's team started by testing the hypothesis that inhibiting PIM kinases would work synergistically with rapamycin, an immunosuppressant drug, to control GVHD development. Using a preclinical mouse model, they looked at how knocking out each PIM isoform, individually and in various combinations, affected GVHD induction.

"We thought that, if these kinases work in parallel, then blocking all three pathways at the same time would improve therapeutic effectiveness," explains Yu. "But when we tested each one, we saw that PIM-2 really stood out from the others and dominated the effect. We found that T cells which lacked PIM-2 had dramatically increased activation and pathogenicity to cause GVHD."

In contrast, blocking PIM-2 created highly activated, aggressive T cells for attacking cancer. "Our results in the BMT model were very robust. When we transplanted the normal number of T cells (which lacked PIM-2), the mice developed severe GVHD and died super fast-within 10 days. We had to keep reducing the T cell dose," says Yu. The team eventually found that even a dose of only 50,000 PIM-2 deficient T cells led to GVHD, whereas this number of wild-type, control T cells was incapable of inducing GVHD.

These results suggest that PIM-2 kinase plays a dominant role in regulating T cell pathogenicity in inducing GVHD and reveal a previously undefined role for PIM-2: potently inhibiting T cell alloresponses and GVHD induction. Results showed that, while PIM-2 negatively regulates T cells, PIM-1 and PIM-3 positively regulate T cell activation.

"Imagine that the therapy is a car," explains Yu. "If you want it to go faster, you can either step on the gas by boosting molecules that positively regulate the T cells, or you can remove the brakes by blocking molecules that negatively regulate the T cells. Blocking PIM-2 is like removing the brakes from a car so it then has more power to eradicate the malignancy, although at a cost of GVHD as a side effect."

Next, the team investigated PIM-2 blockade in a solid, syngeneic tumor model, transplanting cancer cells into mice that lacked PIM-2. Yu was astonished by the results. "When we injected tumor cell lines, the tumor could not grow in the PIM-2 blocked mice," says Yu. "In control mice, the tumors grew rapidly but mice without the PIM-2 molecule could completely reject the tumor. This was a big surprise. Very few molecules are so powerful."

The finding highlights the potential of PIM-2 blockade as a cancer immunotherapy.

This is the first time that the unique activity of PIM-2 kinase in T cells has been distinguished from its family members, PIM-1 and PIM-3. These findings raise concerns about pan-PIM inhibition, which may have disadvantages when the desired effect is immuno-suppression and T cell anergy. Furthermore, PIM-2 blockade may not be applicable in allogeneic BMT since it may exacerbate GVHD, whereas PIM-1 and PIM-3 blockade may alleviate GVHD.

"This study highlights the need for specific inhibitors and to exercise caution using pan-PIM inhibitors," explains Yu. "The same family of kinases can play distinct roles, so we must be more careful and understand the context of which isoforms we want to block because they may not work in a synergistic way. The lesson is that when we do scientific research, we have to keep an open mind. This kinase family has been extensively studied but we saw something completely unexpected when we studied them in different cells and different systems."
-end-
About MUSC

Founded in 1824 in Charleston, The Medical University of South Carolina is the oldest medical school in the South. Today, MUSC continues the tradition of excellence in education, research, and patient care. MUSC educates and trains more than 3,000 students and residents, and has nearly 13,000 employees, including approximately 1,500 faculty members. As the largest non-federal employer in Charleston, the university and its affiliates have collective annual budgets in excess of $2.2 billion. MUSC operates a 750-bed medical center, which includes a nationally recognized Children's Hospital, the Ashley River Tower (cardiovascular, digestive disease, and surgical oncology), Hollings Cancer Center (a National Cancer Institute designated center) Level I Trauma Center, and Institute of Psychiatry. For more information on academic information or clinical services, visit musc.edu. For more information on hospital patient services, visit muschealth.org.

About MUSC Hollings Cancer Center

The Hollings Cancer Center at the Medical University of South Carolina is a National Cancer Institute-designated cancer center and the largest academic-based cancer research program in South Carolina. The cancer center comprises more than 120 faculty cancer scientists with an annual research funding portfolio of $44 million and a dedication to reducing the cancer burden in South Carolina. Hollings offers state-of-the-art diagnostic capabilities, therapies and surgical techniques within multidisciplinary clinics that include surgeons, medical oncologists, radiation therapists, radiologists, pathologists, psychologists and other specialists equipped for the full range of cancer care, including more than 200 clinical trials. For more information, visit http://www.hollingscancercenter.org

Medical University of South Carolina

Related Cancer Articles:

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.
Oncotarget: Cancer pioneer employs physics to approach cancer in last research article
In the cover article of Tuesday's issue of Oncotarget, James Frost, MD, PhD, Kenneth Pienta, MD, and the late Donald Coffey, Ph.D., use a theory of physical and biophysical symmetry to derive a new conceptualization of cancer.
Health indicators for newborns of breast cancer survivors may vary by cancer type
In a study published in the International Journal of Cancer, researchers from the UNC Lineberger Comprehensive Cancer Center analyzed health indicators for children born to young breast cancer survivors in North Carolina.
Few women with history of breast cancer and ovarian cancer take a recommended genetic test
More than 80 percent of women living with a history of breast or ovarian cancer at high-risk of having a gene mutation have never taken the test that can detect it.
More Cancer News and Cancer Current Events

Trending Science News

Current Coronavirus (COVID-19) News

Top Science Podcasts

We have hand picked the top science podcasts of 2020.
Now Playing: TED Radio Hour

Listen Again: Reinvention
Change is hard, but it's also an opportunity to discover and reimagine what you thought you knew. From our economy, to music, to even ourselves–this hour TED speakers explore the power of reinvention. Guests include OK Go lead singer Damian Kulash Jr., former college gymnastics coach Valorie Kondos Field, Stockton Mayor Michael Tubbs, and entrepreneur Nick Hanauer.
Now Playing: Science for the People

#562 Superbug to Bedside
By now we're all good and scared about antibiotic resistance, one of the many things coming to get us all. But there's good news, sort of. News antibiotics are coming out! How do they get tested? What does that kind of a trial look like and how does it happen? Host Bethany Brookeshire talks with Matt McCarthy, author of "Superbugs: The Race to Stop an Epidemic", about the ins and outs of testing a new antibiotic in the hospital.
Now Playing: Radiolab

Dispatch 6: Strange Times
Covid has disrupted the most basic routines of our days and nights. But in the middle of a conversation about how to fight the virus, we find a place impervious to the stalled plans and frenetic demands of the outside world. It's a very different kind of front line, where urgent work means moving slow, and time is marked out in tiny pre-planned steps. Then, on a walk through the woods, we consider how the tempo of our lives affects our minds and discover how the beats of biology shape our bodies. This episode was produced with help from Molly Webster and Tracie Hunte. Support Radiolab today at Radiolab.org/donate.