黑料吃瓜资源

The fight against cancer is an arms race, and one of the most effective weapons in clinicians鈥� arsenals is immunotherapy. Immune checkpoint therapy has become the standard for treating several types of cancer. However, the Nobel Prize-winning strategy is ineffective for most pancreatic ductal adenocarcinoma (PDAC) patients.

鈥淚mmune checkpoint therapy is only an option in rare cases of PDAC,鈥� 黑料吃瓜资源 (CSHL) Professor Douglas Fearon says. 鈥淚t鈥檚 only effective for patients with a specific subtype of PDAC鈥攖hat鈥檚 less than 5% of all cases.鈥�

Until recently, it was thought that PDAC didn鈥檛 trigger any kind of immune response. In 2023, Fearon and his team confirmed the opposite. Immune cells do go on the attack. But they struggle to infiltrate the deadly tumors, which allows PDAC to avoid destruction. Now, Fearon and former CSHL postdoc Jiayun Li have discovered that a common chemotherapy supplement called folinic acid weakens the cancer鈥檚 defenses in mice. They found that folinic acid elevates levels of two anti-cancer immune molecules within PDAC: natural killer T (NKT) cells and type-I interferons. In mice, this leads to a more effective immune response, slower tumor growth, and longer survival. Fearon says:

鈥淲e discovered that NKT cells enabled type-I interferon to be produced and, as a consequence, adaptive immune killing and expansion of T cells would occur. T cells respond to tumors, but they typically cannot get in there unless type-I interferon is produced. Folinic acid enhances that response.鈥�

PDAC resists immune cells, using a protective shield built from two proteins鈥擟XCR4 and CXCL12. This defensive wall is virtually impenetrable. But when the team treated PDAC tumors with folinic acid, cracks were revealed. The resulting elevated levels of NKT cells and type-I interferons acted like trail markers, highlighting a way past PDAC鈥檚 defenses. Cancer-killing immune cells that had been kept outside the wall were able to slip into the tumor and start fighting back.

The Fearon lab now aims to translate its discovery into new therapeutics. They鈥檝e recently partnered with biotech company Autobahn Labs to develop potential drugs targeting CXCR4 and CXCL12. These may one day make immune checkpoint therapy a regular option in the fight against PDAC.

鈥淭ranslating observations in mice into human therapy has been difficult,鈥� Fearon says. 鈥淏ut if we鈥檙e successful, immunotherapy may one day become a viable choice for all patients with PDAC鈥攁nd every other solid tumor鈥攏ot just in the rare cases we see today.鈥�

Written by: Nick Wurm, Communications Specialist | [email protected] | 516-367-5940

Funding

Lustgarten Foundation, Thompson Family Foundation, Cedar Hill Foundation, Simons Foundation, Mestag Therapeutics, National Institutes of Health, National Cancer Institute

Citation

Li, J., et al., 鈥淚ntratumoral NKT cell accumulation promotes antitumor immunity in pancreatic cancer鈥�, Proceedings of the National Academy of Sciences, July 8, 2024. DOI:

Core Facilites

鈥淭丑别 Animal Shared Resource houses and cares for the animals essential for scientific research. Our staff perform all aspects of animal husbandry, ensure humane care, and assist researchers with highly technical procedures and protocol design and development.鈥� 鈥� Animal Facility Director and Attending Veterinarian Rachel Rubino, DVM

鈥淭丑别 Flow Cytometry Shared Resource offers researchers equipment, training, and assistance with cellular analysis for a variety of applications as well as cell sorting. Our staff oversees equipment maintenance and quality control, trains new users on instrument operation, and assists with assay development and data analysis. We also provide tissue culture facilities for sample preparation and cell maintenance during ongoing flow cytometry experiments.鈥� 鈥� Director Pamela Moody

鈥淭丑别 Microscopy Core Facility provides training, consultation, experimental design and technical assistance to investigators at CSHL in widefield, spinning disk laser scanning or point laser scanning confocal fluorescence microscopy, and super-resolution microscopy. In addition, the Microscopy Shared Resource provides customized state-of-the-art optical imaging and quantitative image analysis applications to support a wide range of scientific endeavors.鈥� 鈥� Director Erika Wee, Ph.D.

鈥淭丑别 Sequencing Technologies and Analysis Shared Resource provides access to an array of high throughput Next Generation Sequencing (NGS) technologies. We offer cutting-edge technology alongside convenient in-house services for a broad range of genetic analysis.鈥� 鈥� NGS Director Sara Goodwin, Ph.D.

鈥淭丑别 Tissue Imaging Shared Resource provides a spectrum of on-demand and researcher-tailored histopathological services, including tissue sampling, processing, embedding, and sectioning, as well as H&E, special, and immunohistochemistry staining. We not only support laser-capture microdissection and whole-slide scanning, but also offer histopathology consultation and instrument training.鈥� 鈥� Manager Kristin Milicich