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August 21, 2018

Identification of Sprouty 1 and Sprouty 2 Provide Basis for New Immunotherapies

  • Researchers at the Gladstone Institutes have identified two molecules, Sprouty 1 and Sprouty 2, that modify the survival of effector T cells and the development of memory CD8 T cells. The team, which published its study (“Lack of Sprouty 1 and 2 enhances survival of effector CD8+ T cells and yields more protective memory cells") in PNAS, believes its findings offer promising potential for immunotherapeutic strategies to combat cancer and chronic infections.

    “Identifying novel pathways that promote robust function and longevity of cytotoxic T cells has promising potential for immunotherapeutic strategies to combat cancer and chronic infections. We show that Sprouty 1 and 2 (Spry1/2) molecules regulate the survival and function of memory CD8+ T cells. Spry1/2 double-knockout (DKO) ovalbumin (OVA)-specific CD8+ T cells (OT-I cells) mounted more vigorous autoimmune diabetes than WT OT-I cells when transferred to mice expressing OVA in their pancreatic β-islets. To determine the consequence of Spry1/2 deletion on effector and memory CD8+ T cell development and function, we used systemic infection with lymphocytic choriomeningitis virus (LCMV) Armstrong. Spry1/2 DKO LCMV gp33-specific P14 CD8+T cells survive contraction better than WT cells and generate significantly more polyfunctional memory T cells. The larger number of Spry1/2 DKO memory T cells displayed enhanced infiltration into infected tissue, demonstrating that absence of Spry1/2 can result in increased recall capacity. Upon adoptive transfer into naive hosts, Spry1/2 DKO memory T cells controlled Listeria monocytogenes infection better than WT cells,” write the investigators.

    “The enhanced formation of more functional Spry1/2 DKO memory T cells was associated with significantly reduced mTORC1 activity and glucose uptake. Reduced p-AKT, p-FoxO1/3a, and T-bet expression was also consistent with enhanced survival and memory accrual. Collectively, loss of Spry1/2 enhances the survival of effector CD8+ T cells and results in the formation of more protective memory cells. Deleting Spry1/2 in antigen-specific CD8+T cells may have therapeutic potential for enhancing the survival and functionality of effector and memory CD8+ T cells in vivo.”

    To fight viral infections, the immune system calls on CD8 T cells to kill the infected cells. The CD8 T cells can also be used in immunotherapy approaches to kill cancer cells, including CAR T-cell therapy.

    "The problem is that CD8 T cells are often exhausted in cancer and chronic infections like HIV, so they die off or stop functioning properly," says Shomyseh Sanjabi, Ph.D., an assistant investigator at the Gladstone Institutes who has been studying this cell type for nearly 15 years. "I've been trying to better understand how these cells develop in order to find ways to help them regain their function and live longer."

    When you initially get exposed to an invading pathogen, such as a virus, CD8 T cells begin to rapidly multiply. At this stage, they are called effector cells and act like foot soldiers, killing infected cells, explains Dr. Sanjabi. Once the pathogen is gone, most effector cells die to ensure they don't begin to attack your own body. 

    The ones that survive become memory cells, which are more like specialized guards, patrolling your body for the same invaders for the rest of your life, she continues, adding that the next time you get exposed to the same pathogen, these memory cells allow your body to respond much more quickly and protect you. 

    Using animal models that Dr. Sanjabi has been developing for the past 10 years, the researchers in her laboratory deleted both Sprouty 1 and Sprouty 2 from CD8 T cells to see what would happen. They found that a larger than usual number of effector cells survive and become memory cells. The team also showed that the resulting memory cells, which lack the Sprouty molecules, actually have better protective capacity against a bacterial pathogen than regular memory cells. 

    They also demonstrated these same memory cells consume less glucose as an energy source than normal CD8 T cells. While effector cells depend on glucose to live, memory cells generally use more fatty acids. 

    "Tumor cells use a lot of glucose, so effector cells have difficulty surviving in the tumor environment because it doesn't have a sufficient source of energy," explains Hesham Shehata, Ph.D., former postdoctoral scholar in Dr. Sanjabi's laboratory and first author of the study. "While memory cells generally don't depend on glucose, our study suggests that effector cells without Sprouty 1 and 2 consume less glucose, so they could survive and function in a tumor environment much better."

    The study offers a new way to increase the number, survival, and function of memory CD8 T cells, which could provide better protection against tumors and pathogenic infections, according to the researchers.

    "By shedding light on the role of Sprouty 1 and 2, our work revealed another layer of the underlying biology of T cells," says Dr. Shehata. "Cells that lack Sprouty 1 and 2 have immense potential not only to fight tumors, but chronic viral infections as well. It's exciting that our study can be applied to multiple contexts."

    In the case of HIV, for instance, deleting the two Sprouty molecules could lead to memory cells that better survive and could effectively kill the activated cells harboring latent virus, one of the main barriers to a cure. 

    As for cancer immunotherapy, recent studies have shown that approaches using memory cells can help reduce tumor sizes or even completely eliminate tumors, as compared to treatments using effector cells that have led to more patients relapsing.

    "There's been great interest within the scientific community to enhance the development and function of memory CD8 T cells, which work better for immunotherapies than effector T cells," says Dr. Sanjabi, who is also an associate professor of microbiology and immunology at Univeristy of California, San Francisco. "Our findings could provide an opportunity to improve future engineering of CAR-T cells against tumors. This could potentially be used in combination with a genome-editing technique like CRISPR that would remove the Sprouty 1 and 2 molecules from the cells to make them more effective." 

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