Boosting immune memory could reduce cancer recurrence
July 15 , 2020

 to this mouse model, they expected that the tumors would not grow or grow more slowly when compared to normal animals, as they had seen when blocking other checkpoint proteins. Instead, they saw no difference at all.

"We were a bit disappointed and thought we had hit a dead end because it looked like removing NRP1 did not impact anti-tumor immunity," said Liu. "But instead of giving up, we asked a different question—does NRP1 change the capability of the immune system to remember the tumor?"

They removed the tumor, waited and grafted cancer cells again in a different location, mimicking how a tumor might come back in a patient who had surgery. They saw a dramatic effect. Mice that had NRP1 genetically deleted on killer T cells were better protected against the secondary tumor and responded more positively to anti-PD1 immunotherapy when compared to normal mice.

Further experiments revealed that neuropilin was controlling the fate of how T cells develop and establish immune memory. Having NRP1 caused the killer T cells to become exhausted and ineffective in fighting cancer cells, particularly long-term, while removing NRP1 resulted in T cells having an increased immune memory—the ability of the immune response to respond more potently when it "sees" a tumor again.

These findings in mice also correlated with studies of T cells isolated from the blood of patients with skin cancer or head and neck cancer. Patients with advanced stage head and neck cancer had higher levels of NRP1 on a subset of "memory" killer T cells and fewer of these cells compared to those with earlier stage disease. In patients with advanced skin cancer treated with various immunotherapies, higher NRP1 levels on killer T cells were associated with a poorer response to treatment and a smaller pool of memory T .

"This is a completely new area of understanding of how anti-tumor immunity is controlled and will present new therapeutic opportunities to promote and enhance a more durable, long-term anti- response in cancer patients," says Vignali.

Drugs that target NRP1 are already being tested in the clinic in combination with anti-PD1 immunotherapies, and these clinical trials will reveal much more about the role of immune memory in fighting , says Vignali. "This is why persistence pays off. When our initial hypothesis turned out to be incorrect, we kept pursuing other possibilities and ended up with an important new discovery."

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