Boosting immune memory could reduce cancer recurrence

Date:
July 15, 2020
Source:
University of Pittsburgh
Summary:
A new study on how immune memory can be targeted and improve
immunotherapy and prevent cancer recurrence.



FULL STORY ========================================================================== Blocking a newly identified "immune memory checkpoint" in immune cells
could improve immunotherapy and help prevent cancers from recurring,
according to new findings in mice and human samples by researchers at
the UPMC Hillman Cancer Center and the University of Pittsburgh School
of Medicine. The research was published this week in Nature Immunology.


========================================================================== Immunotherapy drugs that harness the body's own immune system to fight
cancer have revolutionized the treatment of many cancers. They work by
blocking checkpoint inhibitor proteins like PD1, removing the brakes
from cancer-killing T cells in the immune system. However, only about
a third of patients respond to these drugs.

"There is still much work to be done to improve cancer immunotherapy
because only a small group of people benefit, and even among those, we
see many tumors relapsing," said Dario A.A. Vignali, Ph.D., who holds
the Frank Dixon Chair in Cancer Immunology at Pitt's School of Medicine
and is the co-leader of the Cancer Immunology and Immunotherapy program
at the UPMC Hillman Cancer Center.

"Our findings point to an important new biological anti-tumor mechanism
that we can exploit to provide durable, long-term immune response
against tumors." Vignali and his colleagues discovered that a protein
called Neuropilin-1 (NRP1) plays an important role in suppressing immune responses to cancer.

"We knew NRP1 was present on the surface of other T cells, but we
wondered whether it somehow altered the function of the killer T
cells," said Chang "Gracie" Liu, Ph.D., a postdoctoral researcher in
Vignali's lab and first author of the publication. "We thought it might function like any other immune checkpoint molecule and that blocking it
would prevent tumors from growing." Liu and her colleagues created a genetically modified mouse that had NRP1 removed specifically from the
surface of only killer T cells. When they grafted tumor cells 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 cells.

"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-tumor 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 cancer, 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."

========================================================================== Story Source: Materials provided by University_of_Pittsburgh. Note:
Content may be edited for style and length.


========================================================================== Journal Reference:
1. Chang Liu, Ashwin Somasundaram, Sasikanth Manne, Angela M. Gocher,
Andrea
L. Szymczak-Workman, Kate M. Vignali, Ellen N. Scott, Daniel
P. Normolle, E. John Wherry, Evan J. Lipson, Robert L. Ferris,
Tullia C. Bruno, Creg J. Workman, Dario A. A. Vignali. Neuropilin-1
is a T cell memory checkpoint limiting long-term antitumor
immunity. Nature Immunology, 2020; DOI: 10.1038/s41590-020-0733-2 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/07/200715095454.htm

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