A recent study led by researchers at NYU Langone Health has identified a protein produced by stressed cancer cells that helps lung and pancreatic tumors evade detection by the immune system. The findings, published in Nature on February 18, highlight lipocalin 2 (LCN2) as a key player in enabling tumors to resist immune attacks.
The research team discovered that drugs designed to block LCN2 slowed tumor growth in mice, making aggressive cancers more susceptible to immunotherapies. These therapies are intended to support the body’s immune system in targeting and destroying cancer cells.
Cancer cells often experience ongoing stress due to rapid growth and limited nutrients. This activates the integrated stress response (ISR), which triggers production of activating transcription factor 4 (ATF4). ATF4 then initiates various genes that help cancer cells survive. According to the study, ATF4 also directs the release of LCN2, which protects tumors from immune surveillance.
“Stressed cancer cells have learned to call for help through LCN2, which shields them from the immune system,” said Thales Y. Papagiannakopoulos, PhD, associate professor in the Department of Pathology at NYU Grossman School of Medicine.
The study found that LCN2 influences macrophages—immune cells present in large numbers within tumors—to adopt an immunosuppressive role. This prevents T cells, which can kill cancer cells, from entering the tumor environment.
While ATF4 operates inside tumor cells and is difficult to target with drugs, LCN2 is released outside of these cells and can be blocked more easily. Researchers developed an antibody therapy that binds to LCN2 and blocks its activity. This approach allowed T cells back into tumors when tested in mice.
Experiments showed that mice lacking LCN2 experienced slower tumor growth if their immune systems were intact. Analysis of human samples revealed that high levels of LCN2 correlated with shorter median survival times among lung and pancreatic cancer patients compared with those who had lower levels.
Treatment with an anti-LCN2 antibody increased T cell infiltration into mouse tumors and reduced tumor size. Combining this antibody with an existing immunotherapy drug further improved survival rates in mice with aggressive lung cancers.
“Our results provide a clear rationale for developing therapies that target LCN2 in lung cancer patients,” said Shohei Koide, PhD, professor at NYU Grossman School of Medicine and director of Cancer Biologics at Perlmutter Cancer Center. “We also want to explore whether this mechanism is active in other cancer types that resist immunotherapy.”
The multi-institutional study included contributions from scientists at NYU Langone Health; University of Pittsburgh; University of California, San Diego; MIT; Université Paris Cité; Sungkyunkwan University School of Medicine; Moores Cancer Center; Lunit Inc.; Aethon Therapeutics; Revalia Bio; Argenx BVBA; Black Diamond Therapeutics; Puretech Health; Eisai; and others.
Funding for this research came from several National Institutes of Health grants as well as support from organizations such as the American Cancer Society Research Scholar Grant and National Science Foundation CAREER grant.
Disclosures include funding received by Dr. Papagiannakopoulos from several pharmaceutical companies unrelated to this work, consulting fees received by Dr. Koide who also holds equity in related biotechnology firms, and patent filings connected to aspects of this research by several authors—all managed according to NYU Langone Health policies.
NYU Langone Health has been recognized nationally for patient outcomes and quality care across its network facilities and medical schools.
