Making Resistant Tumors Vulnerable to Treatment
Cedars-Sinai Cancer Investigators Identify Cell Subtype That Blocks Immunotherapy From Soft Tissue Sarcoma Tumors
Some soft tissue sarcomas, a rare type of cancerous tumor, are resistant to immunotherapy and chemotherapy treatment. But Cedars-Sinai Cancer investigators, in a study published in the peer-reviewed journal Nature Communications, have identified a new way to overcome this resistance. This could lead to new treatments for this disease and other cancer types.
“We identified a new subtype of cells surrounding therapy-resistant soft tissue sarcomas,” said Jlenia Guarnerio, PhD, a research scientist at Cedars-Sinai Cancer and senior author of the study. “These cells secrete a molecular ‘Velcro’ called CXCL16 that traps immune cells, especially T cells, and keeps them from entering the tumor. With very few T cells inside the tumor, available immunotherapies aren’t effective.”
Soft tissue sarcomas originate in muscle, fat, blood vessels, nerves, tendons and joint lining, and can occur anywhere in the body. Some of these tumors do not respond to immunotherapy, which helps the body’s own immune system fight cancer cells, said Marina Broz, a PhD student in the Guarnerio Lab at Cedars-Sinai and first author of the study.
“Previous studies have shown that cells called cancer-associated fibroblasts prevent immune cells from entering these tumors, leading to therapy resistance, but the way they achieve this is poorly understood in many cancers and particularly in soft tissue sarcomas,” Broz said.
Investigators found a particular subtype of cancer-associated fibroblasts surrounding therapy-resistant soft tissue sarcomas in laboratory mice.
“These are the cells that are trapping T cells outside the tumors,” Broz said. “And we noted that they rely on glucose to make energy, which turned out to be the key to turning non-responding tumors into responders.”
When investigators treated the mice with a glycolysis inhibitor to stop the cells from using glucose, the fibroblasts no longer secreted CXCL16—and T cells invaded the previously therapy-resistant tumors. This dramatically improved the abundance of T cells, thus making the tumors more vulnerable to chemotherapy as well.
“Without the inhibitor, the tumors were barely responsive to therapy,” Guarnerio said. “The inhibitor alone didn’t reduce tumor growth at all, but in combination with chemotherapy it significantly reduced tumor growth.”
Because glycolysis inhibitors aren’t safe for patients, investigators will work to develop a therapy to target CXCL16, said Guarnerio, who is also an assistant professor of Radiation Oncology and Biomedical Sciences at Cedars-Sinai.
“Targeting CXCL16 could also improve outcomes for patients with other types of immunotherapy-resistant tumors,” Guarnerio said. “We would like to see if we can engineer a therapy to improve treatment response in all tumor types with poor T cell infiltration.”
Dan Theodorescu, MD, PhD, director of Cedars-Sinai Cancer and the PHASE ONE Distinguished Chair, said that the study is an example of translational research that may produce targeted therapies.
“This work represents our commitment at Cedars-Sinai Cancer to the promise of precision medicine, which may produce targeted therapies and further enhances our clinical adult and pediatric sarcoma program,” Theodorescu said.
Additional Cedars-Sinai authors participating in this study included Emily Y. Ko, Kristin Ishaya, Jinfen Xiao, Marco De Simone, Xen Ping Hoi, Roberta Piras, Basia Gala, Fernando H. G. Tessaro, and Anja Karlstaedt.
Other authors included Sandra Orsulic, Amanda W. Lund, and Keith Syson Chan.
Funding: J.G. was supported by the K99/R00 grant (CA212200) and R01 (CA258265) for the execution of this work. Additionally, J.G. was supported by grants from the Sarcoma Foundation of America (Grant 2019 SFA 15–19), and the Cedars-Sinai Cancer Accelerator Award. M.B. was supported by a National Cancer Institute F31 fellowship (1F31CA284888). K.S.C was supported by R01CA175397, R01CA175397-Supplement, U54CA274375. X.P.H received funding from U54CA274375. A.W.L. received support from the Cancer Research Institute (Lloyd J. Old STAR Award). A.K. was supported by the National Heart, Lung and Blood Institute (R00 HL141702) and the Leukemia Research Foundation New Investigator Award (Grant No. 941997).
Read more on the Cedars-Sinai Blog: Immunotherapy – The Fourth Pillar of Cancer Care