Advancing the study of T cells to improve immunotherapy

January 06, 2021

DALLAS - Jan. 6, 2020 - UT Southwestern scientists have developed a new method to study the molecular characteristics of T cells, critical immune cells that recognize and attack invaders in the body such as viruses, bacteria, and cancer.

The approach, described today in the journal Nature Methods, enables researchers to more easily analyze the roles of T cell receptors (TCRs) - the molecules on the surfaces of T cells that are responsible for recognizing pathogens.

"This could lead to a better understanding of how T cells work as well as new ways to harness T cells to fight disease," says study leader Tao Wang, Ph.D., assistant professor of population and data sciences and a member of the Quantitative Biomedical Research Center at UTSW.

While some immune cells can simultaneously attack different pathogens, T cells are more targeted - every individual T cell has a distinct set of T cell receptors (TCRs) on its surface. Each receptor usually recognizes only one specific molecule, or "antigen." One TCR, for instance, might bind only to a protein found in lung cancers, while a different TCR might bind just to an influenza virus. When a T cell encounters an antigen that binds to one of its TCRs, it becomes activated, prompting an immune response. To ward off the diverse set of potential invaders, humans have millions of different T cells in their bodies.

Scientists have attempted to study what makes different T cells and TCRs more or less effective, hampered so far by a lack of information about what various TCRs do. Generally, they assume that TCRs that look alike must bind to similar antigens, and that all TCRs activate T cells in a similar way.

To eliminate this guesswork, the research team developed a statistical model combining two existing technologies: TCR analysis, which measures a person's TCR diversity, and single-cell RNA sequencing, which identifies the particular genes that are turned on or off in a T cell. Combining these technologies has been challenging since they both generate many thousands of pieces of data per experiment, and the data comes in two different forms. The new model, dubbed Tessa, uses powerful statistical methods to bridge this gap. Tessa reveals what happens to an individual T cell when its TCR recognizes an antigen, and in what way TCRs impact the function of the T cells. (Tessa stands for TCR functional landscape estimation supervised with scRNA-sequencing analysis.)

Using Tessa, the researchers studied 100,288 T cells from both healthy people and cancer patients. In cancer patients, they discovered that the variety of TCRs in T cells has a weaker influence on the functional status of T cells than on those found in healthy patients. This is likely because a plethora of other immune molecules, secreted into the tumor micro-environment, are influencing T cell activity in other ways. This observation - and others that are likely to result from more widespread use of Tessa - could have implications for scientists designing immune-based cancer treatments.

David Gerber, M.D., professor of internal medicine and population and data sciences, and associate director of clinical research in the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern, believes this work provides a completely new way of using single T cell sequencing data. "We envision deploying this promising tool to study the roles of T cells in immune-related adverse events caused by cancer immunotherapy through a recently funded NIAID U01 award," he says.

"Previous techniques have involved a lot of guessing when it comes to the exact function of T cells and how T cell receptors associate with function," adds Todd Aguilera, M.D., Ph.D., a UTSW assistant professor of radiation oncology, and an expert in immunotherapy, who is also collaborating with Wang. "I believe this method could help the identification of the most promising TCRs for personalized TCR-based immunotherapy and better define productive immune responses to guide identification of the optimal immunotherapy strategies."
Other researchers on the study were Ze Zhang (first author), a UTSW graduate, Hongyu Liu, an exchange scholar at UTSW, and Danyi Xiong and Xinlei Wang of Southern Methodist University. This research was supported by funds from the National Institutes of Health (CCSG 5P30CA142543) and the Cancer Prevention and Research Institute of Texas (RP190208).

About UT Southwestern Medical Center

UT Southwestern, one of the premier academic medical centers in the nation, integrates pioneering biomedical research with exceptional clinical care and education. The institution's faculty has received six Nobel Prizes, and includes 23 members of the National Academy of Sciences, 17 members of the National Academy of Medicine, and 13 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 2,500 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in about 80 specialties to more than 105,000 hospitalized patients, nearly 370,000 emergency room cases, and oversee approximately 3 million outpatient visits a year.

UT Southwestern Medical Center

Related Cancer Articles from Brightsurf:

New blood cancer treatment works by selectively interfering with cancer cell signalling
University of Alberta scientists have identified the mechanism of action behind a new type of precision cancer drug for blood cancers that is set for human trials, according to research published in Nature Communications.

UCI researchers uncover cancer cell vulnerabilities; may lead to better cancer therapies
A new University of California, Irvine-led study reveals a protein responsible for genetic changes resulting in a variety of cancers, may also be the key to more effective, targeted cancer therapy.

Breast cancer treatment costs highest among young women with metastic cancer
In a fight for their lives, young women, age 18-44, spend double the amount of older women to survive metastatic breast cancer, according to a large statewide study by the University of North Carolina at Chapel Hill.

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.

Read More: Cancer News and Cancer Current Events is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to