t-cells Archives - Sanford Burnham Prebys
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What SBP Scientists are Researching to Battle Skin Cancer

AuthorHelen I. Hwang
Date

May 16, 2017

Skin cancer is one of the most common of all cancers, and melanoma accounts for about 1 percent of skin cancers. However, melanoma causes a large majority of deaths from that particular type of cancer. Alarmingly, rates of skin cancer have been on the rise in the last 30 years. Here in Southern California, our everlasting summer comes with a price. Exposure to sun increases our risk to melanoma.

Melanoma occurs when the pigment-producing cells that give color to the skin become cancerous. Symptoms might include a new, unusual growth or a change in an existing mole. Melanomas can occur anywhere on the body.

At Sanford Burnham Prebys Medical Discovery Institute (SBP), we have several researchers working on the causes of melanoma and discovering new ways to treat this deadly disease.

Here is a roundup of SBP’s latest research:

Key findings show how melanoma develops in order to identify potential therapeutic targets

Ze’ev Ronai, PhD
Professor and SBP Chief Scientific Advisor

Ronai’s laboratory has been studying how rewired signaling networks can underlie melanoma development, including resistance to therapy and metastatic propensity. One player in that rewiring is a protein called ATF-2, which can switch from its usual tumor-preventive function to become a tumor promoter when combined with a mutation in the human gene called BRAF.

Ronai’s work on a protein, ubiquitin ligases, led to the identification of RNF125 as an important regulator of melanoma resistance to a common chemotherapy drug. RNF125 impacts melanoma resistance by its regulation of JAK2, an important protein kinase which could play an important role in melanoma resistance to therapy.

Work on the ubiquitin ligase Siah2 identified its important role in melanoma growth and metastasis, and its contribution to melanomagenesis. Melanoma is believed to be a multi-step process (melanomagenesis) of genetic mutations that increase cell proliferation, differentiation, and death.

Work in the lab also concern novel metabolic pathways that are exploited by melanoma for their survival, with the goal of identifying combination drug therapies to combat the spread of melanoma. Earlier work on the enzyme PDK1 showed how it can be a potential therapeutic target for melanoma treatment.

Immunotherapy discovery has led to partnership with Eli Lilly

Linda Bradley, PhD
Professor, Immunity and Pathogenesis Program, Infectious and Inflammatory Diseases Center

Bradley’s group is focused on understanding how anti-tumor T cells can be optimized to kill melanoma tumors. They discovered an important molecule (PSGL-1) that puts the “break” on killer T cells, allowing melanoma tumors to survive and grow. Using animal models, they removed this “break” and T cells were able to destroy melanoma tumors. They have extended their studies and found that in melanoma tumors from patients, T cells also have this PSGL-1 “break”. Bradley’s lab has partnered with Eli Lilly to discover drugs that can modulate PSGL-1 activity in human disease that may offer new therapies for patients.

Knocking out a specific protein can slow melanoma growth 

William Stallcup, PhD
Professor, Tumor Microenvironment and Cancer Immunology Program

The danger of melanomas is their metastasis to organs, such as the brain, in which surgical removal is not effective. By injecting melanoma cells into the brains of mice, we have shown that the NG2 protein found in host tissues makes the brain a much “friendlier” environment for melanoma growth.

Specifically, NG2 is found on blood vessel cells called pericytes and on immune cells called macrophages. The presence of NG2 on both cell types improves the formation of blood vessels in brain melanomas, contributing to delivery of nutrients and thus to accelerated tumor growth. Genetically knocking out NG2 in either pericytes or macrophages greatly impairs blood vessel development and slows melanoma growth.

Mysterious molecule’s function in skin cancer identified

Ranjan Perera, PhD
Associate Professor, Integrative Metabolism Program

Ranjan’s research uncovered the workings of a mysterious molecule called SPRIGHTLY that has been previously implicated in colorectal cancer, breast cancer and melanoma. These findings bolster the case for exploring SPRIGHTLY as a potential therapeutic target or a biological marker that identifies cancer or predicts disease prognosis.

 Drug discovery to help babies has led to a clinical trial at a children’s hospital

Peter D. Adams, PhD
Professor, Tumor Initiation and Maintenance Program

Approximately 1 in 4 cases of melanoma begins with a mole, or nevus. Genetic mutations can cause cells to grow uncontrollably. By investigating how this occurs, we can understand why melanoma develops from some moles, but not others.

Babies born with a giant nevus that covers a large part of the body have especially high risk of melanoma, and the nevus cells can spread into their spine and brain. Adams’ research identified a drug that deters the cells from growing. The drug identified will be used in a clinical trial at Great Ormond Street Children’s Hospital in London, England that may help babies with this debilitating disease.

Discovery of a receptor mutation correlates with longer patient survival

Elena Pasquale, PhD
Professor, Tumor Initiation and Maintenance Program

Pasquale’s work has included whether mutations in the Eph receptor, tyrosine kinases, play a role in melanoma malignancy. Eph receptor mutations occur in approximately half of metastatic melanomas. We found that some melanoma mutations can drastically affect the signaling ability of Eph receptors, but could not detect any obvious effects of the mutations on melanoma cell malignancy.

Bioinformatic analysis of metastatic melanoma samples showed that Eph receptor mutations correlate with longer overall patient survival. In contrast, high expression of some Eph receptors correlates with decreased overall patient survival, suggesting that Eph receptor signaling can promote malignancy.

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Rebooting the immune system after a bone marrow transplant

AuthorJessica Moore
Date

August 30, 2016

After a bone marrow transplant, it can take months for the number of T cells to reach healthy levels. Because T cells are crucial for launching an effective immune response, this leaves patients—usually cancer survivors whose immune systems were knocked out by chemotherapy—vulnerable to infections for longer. However, new research, to which Carl Ware, PhD, professor and director of the Infectious and Inflammatory Disease Center, contributed, identifies a novel target for immunotherapeutics to shorten this recovery time.

“This study shows that the lymphotoxin β receptor controls the entry of T cell progenitors into the thymus, the organ where T cells mature,” said Ware. “Future compounds that activate this receptor may help transplants give rise to functional T cells faster.”

Within the overall immune response against invading bacteria, viruses, and other pathogens, T cells are the field officers and special forces. Helper T cells send chemical signals to get other parts of the immune system involved, and cytotoxic T cells recognize and kill infected cells directly. They’re ‘trained’ to distinguish threats from the cells of the body in the thymus, where T cell progenitors that react to normal, uninfected cells are eliminated.

Publishing in the Journal of Immunology, the team, led by William Jenkinson, PhD, and Graham Anderson, PhD, of the University of Birmingham, looked at the importance of various receptors in letting T cell progenitors into the thymus, and found that only the lymphotoxin β receptor was required.

Significantly, the researchers also showed that stimulating the lymphotoxin β receptor boosted the number of transplant-derived T cells.

“Post-transplantation, T cell progenitors can struggle to enter the thymus, as if the doorway to the thymus is closed,” said Anderson. “Our work points to a way to ‘prop open’ the door and allow these cells to enter and mature.”

Ware and his lab have made many contributions to understanding how the lymphotoxin β receptor, as well as other related receptors, affect immunity and inflammation.

“The lymphotoxin β receptor is important not only in the thymus, but also at sites of inflammation and infection,” Ware added. “Further investigation of the effects of activating it throughout the body will determine whether this treatment approach is feasible, or perhaps should be targeted to the thymus.”

The paper is available online here.

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Study reveals protein that dials immune responses up and down

AuthorJessica Moore
Date

May 25, 2016

Research led by scientists at the Sanford Burnham Prebys Medical Discovery Institute (SBP) has identified a new regulator of immune responses. The study, published recently in Immunity, sheds new light on why T cells fail to clear chronic infections and eliminate tumors. The findings open the door for a new approach to modulating T cell responses in many clinical settings, including infections, autoimmune diseases, and tumors that are unresponsive to currently available therapies. Continue reading “Study reveals protein that dials immune responses up and down”

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Scientists find optimal method for generating regulatory T cells to treat autoimmune disease

Authorjmoore
Date

March 11, 2016

While we normally think of T cells as recognizing invaders, their roles are more complex. For example, some T cells, called regulatory T cells (Tregs) suppress conventional T cells’ immune responses. Because conventional T cells can escape normal controls and drive autoimmune diseases such as rheumatoid arthritis and type 1 diabetes, as well as rejection of transplants, Tregs are increasingly viewed as a way to rein in autoimmune diseases. Continue reading “Scientists find optimal method for generating regulatory T cells to treat autoimmune disease”

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Research suggests new way to prevent HIV-associated brain injury

Authorsgammon
Date

December 5, 2014

For about 50 percent of HIV-1-infected people, things as simple as buttoning a shirt, remembering the alphabet, and handling money may become compromised by a disorder known as HIV-induced brain injury. The condition occurs when receptors and proteins in an HIV-infected immune system produce toxic substances that lead to brain- and nerve-cell death. There is currently no treatment available for the more than 600,000 affected individuals in the U.S. In a new study by Sanford-Burnham researchers, blocking CCR5—an HIV co-receptor—was found to protect against brain injury and impairment of learning and memory. The findings, reported in The Journal of Immunology, create a new approach to treating HIV-induced brain injury and may help our understanding of the potential involvement of CCR5 in other diseases of the brain. Continue reading “Research suggests new way to prevent HIV-associated brain injury”