The molecular underpinnings of T cell exhaustion
La Jolla Institute for Allergy and Immunology News Mar 27, 2017
LJI investigators scrutinize the genome of non–functional immune cells as a means to create more effective immunotherapies.
One reason we survive into adulthood is that cell–killing T cells usually recognize and eliminate cancerous or pathogen–infected cells. But prolonged overactivity of immune cells summoned to a tumor or infection site can render them useless to dispatch invaders, a cellular state immunologists call Âexhaustion. Fortunately, cancer researchers are devising effective immunotherapies to counter exhaustion and re–motivate immune cells to eradicate a patientÂs tumor.
To bolster these approaches, La Jolla Institute for Allergy and Immunology (LJI) scientists Anjana Rao, PhD, and Patrick Hogan, PhD, are asking what genes become activated when immune cells flag. Their new study, published in the online issue of Proceedings of the National Academy of Science journal, reports first that the DNA structure of exhausted T cells differs from that of normal cells. That discovery led them to compile an updated list of candidate DNA binding proteins that may drive exhaustion programs in immune cells. This work provides researchers with additional factors that could be targeted as part of next–generation immunotherapies.
ÂImmunotherapies are showing real effectiveness in patients, but in some cases effectiveness is short–lived. says Hogan, a professor in the Division of Signaling and Gene Expression and a study author. ÂTo continue to make real advances in the clinic we must keep refining these approaches. One way we do that is by understanding how tumors talk immune cells out of doing their job.Â
To observe how T cells lose their steam in the tumor environment, the team prepared two populations of genetically engineered T–cells: a test group that recognizes a tumor antigen and thus can be rendered non–functional by chronic exposure to the tumor (the exhaustion group), and a control group that remains functional because it doesnÂt recognize any tumor antigen. That readied them to compare what goes awry molecularly inside exhausted compared to fully competent T cells.
They did that by injecting the T cells into model mice bearing melanomas to monitor how each test group would behave in a real tumor. Both populations congregated in tumors, but over time cells of the exhaustion group began to display high levels of Âexhaustion markers (as anticipated), because they were overstimulated by the tumor antigen. Among those markers was PD–1, a molecular bad actor notorious for blocking cell–killing capacity of T cells (PD–1 inhibitors, for example, captured headlines two years ago when proven effective against some forms of metastatic melanoma). By contrast, control T cells that the group recovered from a tumor displayed much lower levels of exhaustion markers, simply because they did not perceive the tumor. The next step was to identify genes switched on in the exhausted group and determine how that happened.
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One reason we survive into adulthood is that cell–killing T cells usually recognize and eliminate cancerous or pathogen–infected cells. But prolonged overactivity of immune cells summoned to a tumor or infection site can render them useless to dispatch invaders, a cellular state immunologists call Âexhaustion. Fortunately, cancer researchers are devising effective immunotherapies to counter exhaustion and re–motivate immune cells to eradicate a patientÂs tumor.
To bolster these approaches, La Jolla Institute for Allergy and Immunology (LJI) scientists Anjana Rao, PhD, and Patrick Hogan, PhD, are asking what genes become activated when immune cells flag. Their new study, published in the online issue of Proceedings of the National Academy of Science journal, reports first that the DNA structure of exhausted T cells differs from that of normal cells. That discovery led them to compile an updated list of candidate DNA binding proteins that may drive exhaustion programs in immune cells. This work provides researchers with additional factors that could be targeted as part of next–generation immunotherapies.
ÂImmunotherapies are showing real effectiveness in patients, but in some cases effectiveness is short–lived. says Hogan, a professor in the Division of Signaling and Gene Expression and a study author. ÂTo continue to make real advances in the clinic we must keep refining these approaches. One way we do that is by understanding how tumors talk immune cells out of doing their job.Â
To observe how T cells lose their steam in the tumor environment, the team prepared two populations of genetically engineered T–cells: a test group that recognizes a tumor antigen and thus can be rendered non–functional by chronic exposure to the tumor (the exhaustion group), and a control group that remains functional because it doesnÂt recognize any tumor antigen. That readied them to compare what goes awry molecularly inside exhausted compared to fully competent T cells.
They did that by injecting the T cells into model mice bearing melanomas to monitor how each test group would behave in a real tumor. Both populations congregated in tumors, but over time cells of the exhaustion group began to display high levels of Âexhaustion markers (as anticipated), because they were overstimulated by the tumor antigen. Among those markers was PD–1, a molecular bad actor notorious for blocking cell–killing capacity of T cells (PD–1 inhibitors, for example, captured headlines two years ago when proven effective against some forms of metastatic melanoma). By contrast, control T cells that the group recovered from a tumor displayed much lower levels of exhaustion markers, simply because they did not perceive the tumor. The next step was to identify genes switched on in the exhausted group and determine how that happened.
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