August 13, 2021

A new approach to cancer immunotherapy Study highlights a promising strategy for blocking an off switch on immune cells.

August 13, 2021

LA JOLLA, CA A team headed by scientists at Scripps Research has devised an immune cell-boosting technique that may enable potent new cancer treatments.

The scientists, whose work is described in ACS Central Science, found a way to target Siglec-7, a protein that normally acts like an off-switch on immune cells called human natural killer (NK) cells.

NK cells are natural cancer-fighters, and researchers have been exploring ways to use them as cancer treatments, but many tumors have the ability to blunt NK cell attacks by exploiting off-switches such as Siglec-7.

The scientists showed, however, that by adding relatively small doses of a designer, sugar-like molecule that binds to Siglec-7 proteins, they could induce the release of the Siglec-7 proteins from NK cells, boosting their tumor-killing power.

In principle, we could treat NK cells in this way to reduce their Siglec-7 proteins, thus increasing their anti-tumor potency before the cells are infused therapeutically into cancer patients, says study senior author Peng Wu, PhD, associate professor in the Department of Molecular Medicine at Scripps Research.

Tumors commonly defend themselves from immune attack by producing molecules that effectively shut down immune cells in their vicinity. They often achieve this by exploiting off-switch or dimmer-switch mechanisms that exist on immune cells mechanisms that normally help keep immune cells from becoming overactive and causing unnecessary damage to healthy tissues in the body.

The Importance of Blocking Off-Switches

Scientists in recent decades have begun uncovering these off-switch or dimmer-switch pathways, and developing treatments that block them to boost the immune system's cancer-fighting ability. For example, drugs that block the so-called PD-1 off-switch, on immune cells called T cells, have had astounding successes in some cases, curing patients who had advanced, metastatic cancers. But most tumors are not completely killed by such treatments and that has prompted scientists to look for other off-switches that such tumors may be exploiting.

Siglec proteins, which appear on many immune cells, are now suspected of being among the off-switches that tumors exploit to withstand PD-1 blockers and other cancer immunotherapies. Scientists therefore are racing to find ways to block Siglecs too.

Siglec-7s are the dominant Siglecs on NK cells. Wu and his colleagues found in their study that they could reduce the quantity of Siglec-7 proteins on NK cells by adding small doses of a sugar-like molecule called FTMCNeu5Ac an engineered version of the sugar-like molecule that tumor cells normally use to activate Siglec-7 and shut down NK cells. At the right dose range, the reduction of Siglec-7 brought about by FTMCNeu5Ac dramatically boosted the ability of NK cells to kill cancer cells in lab-dish cultures suggesting this approach as one that might be used to super-charge NK cell-based cancer therapies.

A Surprise Finding

The study also included a surprising and important finding on the basic biology of Siglec-7 in the context of NK cell encounters with cancer cells. Scientists studying Siglec proteins have widely assumed that cancer cells naturally tend to produce large quantities of Siglec-7-binding molecules ( ligands ) in order to defeat NK cells wherever they encounter them. However, Wu and colleagues found otherwise.

It's not the case that tumor cells naturally have high numbers of Siglec-7 ligands and normal cells do not, Wu says. We found instead that tumor cells typically have normal numbers of Siglec-7 ligands, and only get more of these ligands as a defensive response when they actually encounter an NK cell.

Wu and his colleagues are now working to develop their Siglec-7-reducing, NK-cell-boosting strategy, and to see if a similar approach will work with other types of Siglec protein on other immune cells. They are collaborating in this effort with the laboratory of Matt Macauley, Ph.D. at University of Alberta and the laboratory of James Paulson, PhD, Cecil H. and Ida Green Professor and Co-Chair of the Department of Molecular Medicine at Scripps Research, and developer of the Siglec-7-binding ligand used in the study.

Modulation of Siglec 7 Signaling Via In Situ-Created High-Affinity cis-Ligands was co-authored by Senlian Hong, Chenhua Yu, Emily Rodrigues, Yujie Shi, Hongmin Chen, Peng Wang, Digantkumar Chapla, Tao Gao, Ruoxuan Zhuang, Kelley Moremen, James Paulson, Matthew Macauley, and Peng Wu.

Funding was provided by the National Institutes of Health (R01AI154138, P41GM103390, P01GM107012, R01GM130915, R01AI050143, P01HL107151, and U19AI136443).

Cancer Molecular Medicine Wu, Peng

LINK:	https://www.scripps.edu/news-and-events/press-room/2021/20210813-wu-si...
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