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Biomarkers of T Cell Exhaustion in Checkpoint Inhibitor Therapy

In This Article

  • Researchers in the Massachusetts General Hospital Cancer Center looked in the immune landscape of these patients to learn more about what characterized T cell exhaustion
  • T cells are a key part of the immune defenses against cancer, but over time they can lose some function and become "exhausted"
  • Checkpoint inhibitor therapy was developed to overcome the problem of exhausted T cells
  • Most patients don't, however, respond to checkpoint inhibition or later acquire resistance to it

T cells are a key part of the immune defenses against cancer. But after long-term exposure to antigens—substances that evoke an immune response—and other elements in the tumor microenvironment, T cells can lose their function and become "exhausted." Checkpoint inhibitor therapy was developed to overcome the problem of exhausted T cells, allowing the immune system to once again perceive these tumor cells and mobilize against them.

Most patients don't, however, respond to checkpoint inhibition or later acquire resistance to it. This is even true in melanoma, which shows one of the highest response rates to this approach. In an effort to find out why, Nir Hacohen, PhD, director of Center for Cancer Immunotherapy at the Mass General Cancer Center, and Moshe Sade-Feldman, PhD, of the Center for Cancer Research, looked in the immune landscape of these patients to learn more about what characterized cell exhaustion.

"We felt that there hadn't been a detailed analysis of immune response within the tumor," says Dr. Hacohen. Their results were published in the November 2018 issue of Cell.

Good and Bad T Cells

The team looked at melanoma tumors from 32 patients. Four of those tumors had somatic mutations in the B2M, JAK1, STAT1 and IFNGR1 genes, which are all associated with the part of the tumor cell that presents its antigen, a molecular signature. T cells use these signatures to recognize the tumor as a foreign object, "so these mutations being associated with a depressed response from checkpoint inhibitors makes a lot of sense," says Dr. Sade-Feldman. "When tumors lose their ability to present their targets, they become invisible to the eye of the immune system."

They also closely investigated more than 16,000 immune cells in the tumor environment by means of single-cell RNA sequencing. This allowed them to look beyond the genetic makeup of these cells to their particular states. The team focused on CD8 T cells, which directly attack invading cells and were abundant in the tumors.

The team identified two states in which T cells could exist. CD8_G (G for "good") cells were more frequent in tumors that were sensitive to checkpoint therapies and expressed more genes associated with T cell activation and survival. CD8_B (B for "bad") cells were more frequent in tumors that didn't respond to therapies and had markers associated with T cell exhaustion. All tumors had both CD8_G and CD8_B cells, but the proportions differed.

"Our analysis enabled us to find markers so that we could isolate those cells," says Dr. Sade-Feldman. "That opens the door to studying how they function and to isolating the good cells so that you can put them back in a patient."

CD39, TIM3 and a Potential New Therapeutic Approach

The team next looked for marker proteins, expressed on the cell surface, which would easily identify the two categories of CD8 T cells. The surface of CD8_B cells contained two proteins, CD39 and TIM3, and CD8_G cells did not express either protein. The researchers investigated the effects of blocking both proteins found on the "bad" immune cells. Tested on mice with melanoma, blocking either one of these proteins brought about a transient reduction of tumor growth. When both proteins were blocked, tumor size was strongly reduced and 40-day survival increased.

The researchers hope that the markers of good and bad T cells can be used in clinical trials. One use may be to pre-emptively identify which patients will better respond to checkpoint inhibitor therapy. Dr. Sade-Feldman also speculates it may one day be possible to remove a tumor from a patient, isolate the good T cells from that tumor in the lab and then introduce the effective T cells back into the patient to help fight off any remaining cancer.

"I think the field will need more focus on analyzing patient samples in the context of therapy, and that's something we believe is going to make a big difference in the coming years," Dr. Hacohen says. "Since our published paper, many studies have used mouse models to show that the good T cells are critical for the successes of checkpoint therapies and more broadly anti-cancer immunity, supporting our initial findings in cancer patients."

Learn about the Center for Cancer Immunotherapy at the Mass General Cancer Center

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