New target for cancer immunotherapy - NRP1.

Although anti-PD-1/L1 immuno-checkpoint blocking (immune checkpoint, ICB) therapy has revolutionized cancer treatment, only a small percentage (10-30%) of cancer patients show lasting clinical response.
, there is great interest in identifying pre-existing and access to immunodeficiability mechanisms and in developing new treatments to prevent recurrence.
In an article published July 13 in Nature Immunology, researchers at the UPMC Hillman Cancer Center and the University of Pittsburgh School of Medicine revealed their latest findings based on mouse and human sample studies: Blocking an unpronciated immune checkpoint in T-cells, NRP1, improves immunotherapy and helps prevent cancer recurrence.
. Dario A. Vignali, co-author of the Nature Immunology paper, said, "There is still a lot of work to be done to improve cancer immunotherapy, because only a small percentage of people benefit, and even among these people, we are seeing many tumors relapse."
our findings point to an important new anti-tumor mechanism that can provide a long-lasting and long-term tumor immune response.
" Vignali and colleagues found that a protein called neurofibre protein-1 (NRP1) plays an important role in suppressing the immune response to cancer.
NRP1 was originally found to be a neuron and endottor cellular subject necessary for normal embryonic development, axon guidance and angiogenes form, and is also expressed in a variety of immune cell types involved in key immune functions.
NRP1 elevates in regulatory T-cells in cancer patients, suggesting it may be a target for cancer immunotherapy.
, however, the function of NRP1 on other T-cell sub-groups, especially CD8-T cells, remains unclear.
Chang Liu, lead author of the paper, said: "NRP1 is known to exist on the surface of other T-cells, and we wonder if it alters the function of killer T-cells.
we suspect it may function like other immune checkpoint molecules, blocking it prevents tumor growth.
, Liu and colleagues created a genetically modified mouse that specifically removed NRP1 from the surface of its killer T-cells.
When tumor cells were transplanted into the mouse model, they expected the tumor to not grow or grow more slowly than normal animals, as they saw when blocking other checkpoint proteins.
, on the contrary, they don't see any difference.
"We're a little disappointed and feel like we're in a dead end because removing NRP1 doesn't seem to affect anti-tumor immunity," Liu said, "but instead of giving up, we're asking another question: Does NRP1 change the immune system's ability to remember tumors?" They removed the primary tumor from the mice, waited a while, and then re-implanted the cancer cells at another location, simulating a recurrence of the tumor in the surgical patient.
Then came the dramatic effect: mice with missing NRP1 genes in killer T-cells had better preventive effects on secondary tumors, including relatively "cold" tumors such as melanoma in B16.F10 mice, and responded more positively to PD1 immunotherapy.
NRP-1 limits the anti-tumor immune response and anti-PD1 immunotherapy of secondary tumors mediated by CD8-T cells.
(Photo: Nature Immunology) Further experiments have shown that NRP1 controls how T cells develop and build immune memory.
carrying NRP1 depletes killer T-cells and becomes ineffective in fighting cancer cells, especially in the long term.
removal of NRP1 enhances T-cell immune memory, i.e. the immune response is stronger when the tumor is "seen" again.
findings in mice were also linked to studies of T-cells isolated from the blood of patients with skin or head and neck cancer.
compared with early cancer patients, patients with advanced cancer had higher levels of NRP1 in the memory CD8-T cell subset, which was negatively related to the number of memory T cells, the prognostic effect of the disease, and the blocking of immune checkpoints.
NRP1 in cancer patients was associated with poor survival and reduced response to immuno-checkpoint blocking therapy.
( Photo: Nature Immunology) Vignali said: "This is a whole new area of understanding how to control cancer immunity and will provide new treatment opportunities to promote and enhance a longer-lasting, longer-term anti-tumor response for cancer patients.
" Currently, drugs targeting NRP1, such as ASP1948, have been used in combination with anti-PD-1 immunotherapy in clinical trials that will reveal more about the role of immune memory in cancer.
is the reward for sticking to it," said Vignali, a director of the U.S. Government.
when the initial assumptions were proven wrong, we continued to look for other possibilities and finally made an important new discovery.
" in summary, the study found a new immune checkpoint NRP1, which affects the development and function of CD8-T cells in tumors in a cellular way and selectively affects the production of memory pregenitors during the anti-tumor immune response.
this distinguishes NRP1 from other inhibitory subjects such as PD-1, CTLA4, and LAG3, which primarily affect the development and function of effect T cells.
absence of NRP1 does not enhance the anti-tumor response of primary tumors, it has a substantial effect on the development of T-cell memory in secondary tumors.
CD8-T cell NRP1 deficiency joint immuno-checkpoint blocking therapy does improve tumor removal rates, suggesting that combined blocking of PD-1 and NRP1 can lead to longer-lasting systemic anti-tumor immunity and long-term remission in cancer patients.
: 1 s boosting immune memory can reduce cancer resery (Source: Medical press) 2 s Chang Liu et al, Neuropilin-1 is a T cell memory checkpoint limiting long-term antitumor immunity, Nature Immunology (2020). DOI:10.1038/s41590-020-0733-2.