To mobilize T cells against cancer, it may not be enough to “take the brakes off.” It may also be necessary to “hit the gas.” That’s the conclusion reached by Emory Vaccine Center and Winship Cancer Institute scientists. They found that a checkpoint inhibitor, programmed cell death-1 (PD-1), might fail to rouse CD8 T cells to action—unless co-stimulation via the CD28/B7 pathway was also available.

The scientists presented their findings March 9 in the journal Science, in an article entitled “Rescue of Exhausted CD8 T Cells by PD-1–Targeted Therapies Is CD28-Dependent.” In this article, the scientists suggest that CD28's presence on T cells could be a clinical biomarker capable of predicting whether drugs targeting PD-1 will be effective. In addition, the requirement for CD28 suggests that co-stimulation may be missing for some patients, which could guide the design of combination therapies.

“Many studies have assessed expression of inhibitory receptors on exhausted CD8 T cells, but positive co-stimulatory molecules have not been a major focus,” says senior author Rafi Ahmed, Ph.D., director of Emory Vaccine Center.

“We have recently defined the stem-cell-like subpopulation of T cells that can be reinvigorated by PD-1 targeted therapy,” Dr. Ahmed added. “Now we demonstrate that in addition to PD-1 blockade, these cells also require co-stimulatory signals through CD28 to proliferate and differentiate into killer cells. We believe this increase in the number of killer cells is important for successful immunotherapy.”

In the Science paper, Emory Vaccine Center scientists conducted experiments in mice in which they showed that antibodies blocking CD28's interactions with its partner B7, or genetic deletion of CD28, prevented the proliferation of T cells in response to anti-PD-1 agents.

“Here we demonstrate that the CD28/B7 costimulatory pathway is essential for effective PD-1 therapy in tumor-bearing mice and during chronic viral infection,” the authors of the Science paper wrote. “Conditional gene deletion showed a cell-intrinsic requirement of CD28 for CD8 T cell proliferation after PD-1 blockade. B7-costimulation was also necessary for effective PD-1 therapy in tumor-bearing mice.”

To assess the importance of those findings for cancer immunotherapy, the researchers teamed up with physicians from Winship Cancer Institute to analyze samples from lung cancer patients being treated with PD-1-blocking drugs.

“[We] found that CD8 T cells proliferating in blood after PD-1 therapy of lung cancer patients were predominantly CD28 positive,” the Science paper continued. “Taken together these data demonstrate CD28-costimulation requirement for CD8 T cell rescue and suggest an important role for [the] CD28/B7 pathway in PD-1 therapy of cancer patients.”

The scientists monitored T-cell responses in patients' blood and found that most of the CD8 T cells proliferating after PD-1 blockade expressed CD28. Yet, in biopsy samples from early-stage lung cancer patients, the proportion of CD28-positive cells among tumor-infiltrating CD8 T cells was variable, ranging from 20% to 90%. These results suggest that only a subset of tumor-specific CD8 T cells will proliferate after PD-1–directed therapy, Dr. Ahmed noted.

“We observed that in tumors from lung cancer patients, many of the infiltrating PD-1+ CD8 T cells do not express CD28, and thus according to our data from experiments in mice, those CD28-negative cells may not proliferate when the PD-1 pathway is blocked,” commented lead author Alice Kamphorst, Ph.D., a research associate in Ahmed's lab.

She added that the requirement for CD28 co-stimulation points to the importance of nearby antigen-presenting cells providing CD28's partner molecule B7, which is not present on most tumor cells.

The research team is now studying whether CD28 levels on tumor-specific T cells can predict the strength of lung cancer patients' response to PD-1-based drugs or their survival.

“Our study sets the stage to evaluate CD28 as a predictive biomarker for patient selection for immune checkpoint inhibition in patients with cancer, and also paves the way for combination therapy approaches that might result in enhanced effectiveness of immune checkpoint inhibition,” said Winship's deputy director Suresh Ramalingam, M.D. “We are conducting clinical studies to confirm our findings in patients with lung and other cancers.”








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