Narrowing the Search

Narrowing the Search

T cells that react to a patient’s tumor can be used to develop immunotherapy treatments but can be hard to find. Inside of this hourglass, thousands of dots each represent a single T cell from a patient’s tumor sample. CCR researchers examined the cells one by one and grouped them by their mRNA and protein expressions. In this analysis, they found that one group, 2.5% of these cells, included tumor-neoantigen reactive cells (red dots). Using this genetic signature to find these elusive tumor-reactive cells faster should also accelerate the process of creating these immunotherapies for cancer patients. (Gray T cells are CD4+; blue are CD8+ and don’t express CXCL13; red are CD8+ and do express CXCL13.) Credit: Ken-ichi Hanada, CCR, NCI, NIH; iStock

When standard cancer treatments fail to keep cancer in check, cell-based immunotherapies can bolster the body’s own anticancer defenses. These highly customized and sophisticated treatments are created from a patient’s own immune cells and are either selected or engineered to be able to specifically recognize the patient’s tumor as a target. 

In an advance that could accelerate the development of more effective immunotherapy treatments, researchers in the lab of Senior Investigator Steven Rosenberg, M.D., Ph.D., have made tumor-targeting immune cells much easier to find. As reported in Science and Cancer Cell, they have identified patterns of gene activity shared by tumor-reactive T cells.

Usually, one finds tumor-reactive T cells inside a tumor itself. They recognize their targets based on markers on cancer cells. But tumor-reactive T cells make up only a tiny fraction of a person’s army of immune cells. Even inside tumors, they are outnumbered by T cells of other types, so finding them can be challenging.

In meticulous, cell-by-cell analyses of tumor-reactive T cells taken from patient tumors, Research Biologist Frank Lowery, Ph.D., Research Fellow Sri Krishna, Ph.D., and Staff Scientist Ken-ichi Hanada, M.D., Ph.D., found that tumor-reactive T cells shared a characteristic pattern of gene activity. Guided by this gene activity signature, researchers can more easily find T cells that respond to a specific tumor.

Even once located, the tumor-reactive cells may not be strong enough to mount an effective attack. Rosenberg explains that while the T cells isolated from patient tumors are often tumor-reactive, they may also be exhausted and ineffective.

However, researchers can still learn from them how to equip other more vigorous immune cells with receptor molecules so that they can home in on the cancer. “Once we can identify the T cells, we can identify the T-cell receptors and put them into a patient’s normal cells that we can then grow and use for treatment,” Rosenberg says.

Rosenberg’s lab pioneered the use of tumor-infiltrating T cells as cancer immunotherapy decades ago. The approach has been most successful in treating melanoma — sometimes with long-lasting results. Rosenberg and his colleagues have also found that this type of immunotherapy can shrink other types of solid tumors, including colon, liver and cervical cancers.

Steven Rosenberg

Steven A. Rosenberg, M.D., Ph.D.

Surgery Branch

In 2022, they reported on successes in treating advanced breast cancer in the Journal of Clinical Oncology. They found tumor-reactive T cells in the majority of tumor samples they examined, and three women whose disease had failed to respond to other forms of therapy saw their tumors shrink dramatically following treatment with tumor-targeting T cells and a short course of the immunotherapy drug pembrolizumab. One saw her cancer disappear completely and remains cancer-free years after the treatment. 

Still, many patients who receive cell-based immunotherapies do not benefit. Rosenberg and his colleagues want to know what happens when things go right so they can develop treatments that work for more people. “We’re chipping away at this mystery of how to get the immune system to work against the cancer and provide improved treatments for patients,” he says.