Study Describes How T-Cell Responses Search for and Attack Tumor Cells

The steps by which T cells identify and respond to cancer cells are described by UCLA Jonsson Comprehensive Cancer Center scientists in a paper published in Nature. The findings provide insights into why some treatments may be effective for certain patients but not others.

“This is an important step forward in our understanding of what the T-cell responses see in the tumor and how they change over time while they are in the tumor and in circulation in the blood, searching for new tumor cells to attack,” said Cristina Puig-Saus, first author of the study. “The deeper understanding of how the T-cell responses clear metastatic tumor masses will help us design better treatments and engineer T cells in multiple ways to mimic them,” she added.

The researchers adapted advanced gene-editing technology to make observations about immune responses in patients with metastatic melanoma receiving anti-PD-1 checkpoint inhibitor immunotherapy. Although T cells have the ability to detect mutations in cancer cells and eliminate them, leaving normal cells unharmed, cancer cells often evade the immune system.

The investigators showed that when the immunotherapy is effective, it directs a diverse repertoire of T cells against a small group of selected mutations in a tumor. These T-cell responses expand and evolve during the course of treatment, both within the tumor and in the bloodstream. Patients for whom the therapy fails also present a T-cell response against a similarly reduced number of mutations in the tumor, but those immune responses are less focused, and they do not expand during treatment.

“This study demonstrates that patients without response to therapy still induce a tumor-reactive T-cell response,” Puig-Saus said. “These T cells could potentially be isolated and their immune receptors used to genetically modify a larger number of T cells to redirect them against the patient’s tumor. These T cells could be expanded in culture and reinfused into the patients to treat their tumors.”

In the eleven patients studied, seven had a response to PD-1 blockade; four did not. The number of mutations in the tumors ranged between 3,507 and 31. Despite this wide range, the number of mutations seen by tumor-reactive T cells ranged between 13 and one. In patients with clinical benefit from the therapy, the responses were diverse, with a range between 61 and seven different mutation-specific T cells isolated in the blood and the tumor. In contrast, in the patients lacking a response to therapy, the researchers only identified between 14 and two different T cells.

Also, in patients responding to treatment, the researchers were able to isolate tumor-reactive T cells in blood and tumors throughout treatment, but in patients without a response, the T cells were not recurrently detected. Still, the study showed that immune receptors from the T cells isolated from all patients—regardless of response or not—redirected the specificity of immune cells against the tumor, producing antitumor activity.