T-cell behavior determines which tumors respond to treatment – ScienceDaily

Immunotherapy unleashes the power of the immune system to fight cancer. However, immunotherapy does not work for some patients, and new research may explain why. When immune cells called T lymphocytes infiltrate malignant tumors, the genetic program of those T cells and the developmental pathway they then follow can influence their response to immunotherapy and predict the patient’s overall survival, according to a new study from Weill Cornell Medicine -researchers. The results turn the prevailing model of the immune response in melanoma on its head and point to different therapeutic approaches.

In the study, published May 9 in cancer cellThe researchers analyzed thousands of human tumor samples as well as individual human T cells across many data sets and tumor types and compared them to many models of T cell behavior in response to infection, cancer and vaccines, including human vaccines. They found that T cells either get stuck in an early activation state or develop into memory cells that are expanded by current immunotherapy approaches.

“T cells don’t behave in unique ways, but we can understand their behavior and model it in a way that can predict patient outcomes and overall survival,” said senior author Dr. Niroshana Anandasabapathy, associate professor of dermatology and dermatology in microbiology and immunology at Weill Cornell Medicine and practicing melanoma dermatologist at NewYork-Presbyterian/Weill Cornell Medical Center.

Scientists have long known that the immune system can recognize and eliminate tumor cells on its own, but this process sometimes breaks down, leading to the development of cancer. Previous data seemed to support a theory that once a tumor has formed, T lymphocytes see and respond to tumor proteins until they are exhausted and unable to attack the cancer cells. This theory has been used to explain the success of a form of therapy called immune checkpoint blockade, which uses cellular signaling to enhance T-cell responses and reawakens the T-cells’ ability to attack and eliminate the tumor.

However, some patients’ tumors do not respond to immune checkpoint blockade. To find out why, the team began looking at larger datasets and analyzing them more extensively than previous studies.

“We wanted to take a totally agnostic approach to understanding what happens to a T cell once it enters the tumor microenvironment — a really naive, unbiased approach,” said Dr. Anandasabapathy, who is also a member of the Sandra and Edward Meyer Cancer Center and the England Institute for Precision Medicine.

By using large programs with many genetic markers and multiple concurrent genomic strategies to categorize cell fates, Drs. Anandasabapathy and her collaborators were able to reclassify T cells in tumors and better model how they develop. The results show that infiltrating T cells do not meet the same fate in every tumor. In contrast to the standard view, a “failed to start” beyond early activation and conversion to memory rather than exhaustion seemed to be the problem. The accumulation of long-lived memory programs is strongly correlated with overall survival and a successful response to immune checkpoint blockade therapy in melanoma.

In addition to predicting outcomes, investigators hope to find ways to change them. For example, getting T cells past the failure to launch and inducing the formation of tumor-infiltrating memory T cells in patients who lack them might render unresponsive tumors susceptible to immune checkpoint blockade.

While the current work focused on malignant melanoma, the scientists also found that similar phenomena likely underlie differences in patients’ T-cell responses to other cancers, including kidney, bladder, prostate and liver cancer.

“The power of the study really lies in opening new avenues of discovery and proposing more rational therapeutics,” said first author Abhinav Jaiswal, a graduate student in the Weill Cornell Graduate School of Medical Sciences in Dr. Ananda sabapathy.

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