Cancer onset has many potential culprits, but STAT3 — signal transducer and activator of transcription 3, a potent tumor-promoting signaling molecule — is a particularly persistent suspect. Often activated in a variety of cancers, STAT3 organizes a tumor’s growth by helping transformed cancer cells interact with healthy cells in the tumor microenvironment (TME). This makes STAT3 a tempting target for cancer therapies, but help or harm to the patient depends on which immune cells are present.
This area of uncertainty represents an intriguing research opportunity for Hua Yu, Ph.D., the Billy and Audrey L. Wilder Professor in Tumor Immunotherapy and co-leader of the Cancer Immunotherapeutics Program in the Comprehensive Cancer Center at City of Hope. Yu is an expert on STAT3, and as Associate Chair and Professor in the Department of Immuno-Oncology she has been working to develop innovative technologies that will attack STAT3 in a variety of cellular environments and collapse the host tumors.
“If I know it’s good to target STAT3 in a particular kind of immune cell, that’s great,” Yu said. “But I need to know when targeting STAT3 in a particular immune cell is not good for the patient so that we can avoid using that approach. Also, if the therapy doesn’t work, I need to find out what went wrong.”
A new partnership with Ariel Munitz, Ph.D., Associate Professor in the Department of Microbiology and Clinical Immunology at Tel Aviv University’s Sackler School of Medicine, could break new ground in Yu’s efforts. In much of his lab work, Munitz has focused on immune responses and their role in the TME as he strives to develop new immunotherapies. He has a particular expertise in eosinophils, bone marrow-derived white blood cells that have mostly been studied in the context of allergic diseases and parasite infections, but not much in cancers.
“Ariel wanted to study these particular immune cells, which have been a kind of under-investigated area that could play a major role in cancer progression,” Yu said. “Eosinophils may end up being a way to manipulate the tumor to the benefit of patients.”
Munitz sought out Yu as a collaborator to advance his work via a grant from the Jacki and Bruce Barron Cancer Research Scholars’ Program, which was established in 2016 by a generous gift from the Harvey L. Miller Family Foundation to support the exchange of ideas, strategies, and therapies between City of Hope and Israeli investigators sponsored by the Israel Cancer Research Fund (ICRF). This is the second Barron Program grant awarded to Yu, who in 2016 partnered with Shai Izraeli, M.D., now a Research Professor in City of Hope’s Department of Systems Biology and Chair of the Rina Zaizov Pediatric Hematology and Oncology Division at Schneider Children’s Medical Center of Israel, on a study designed to develop new therapeutic approaches for high-risk acute lymphoblastic leukemia (ALL).
Munitz and Yu’s initial research has indicated that STAT3 is indeed activated in eosinophil immune cells in the tumor. With their expertise in these different areas of immunology, the two scientists are now pursuing a hypothesis that eosinophils, which migrate into the TME in a variety of tumors, advance lung and breast cancer metastasis with the help of STAT3.
“There is preliminary data that supports this hypothesis,” Yu said. “Now with the Barron funding, we’re going to accelerate the pace of our cooperation. Ariel is coming to the United States, and I’m so excited that we’re going to discuss the plan in more detail. Because I’m at City of Hope, I have more access to patient specimens and can help make this work more clinically relevant.”
Ultimately, they hope to develop novel cancer treatments that target eosinophils and other unhelpful immune cells present in the TME.
Yu, who earned her Ph.D. in molecular biology from Columbia University, joined City of Hope in 2005 after 10 years as a professor in the immunology program at Moffitt Cancer Center in Tampa, Florida. She has studied the majority of subtypes of immune cells in the TME, but eosinophils were new to her, so Munitz’s proposal immediately struck her as appealing.
“We need to know every single subtype of immune cell to validate whether it’s a good target for cancer therapy,” Yu said. “He and I can really synergize with each other. It’s a very complementary collaboration. We each have our strengths — he’s looking for a mechanism that explains the co-opted immune-cell response, and I’m looking for immune cells I have not worked on before in the context of STAT3.”
Yu, who has been to Israel a few times for work and for conferences, enjoys working with international collaborators. “Sometimes you want scientific exchange with a foreign institute or with people who have different ideas,” she said. “It’s tough to do without funding. This solid Barron Program funding for two years will enable us to do something important.”
“This funding broadens the research scope for Israeli scientists,” Yu continued. “And the same thing applies to me. If we didn’t have the Barron Program, I wouldn’t be thinking about studying eosinophil cells because they weren’t on my radar. They are underexplored, but that doesn’t mean they’re unimportant. It’s an unmet need, so this is a unique opportunity to advance science and gain knowledge. We may come up with additional approaches and future translation so STAT3 targeting can go to clinical testing.”
Yu has patients’ safety foremost in mind in all her research efforts, and the efficacy of any new drugs or therapies is paramount. “The more knowledge I have, the better chance I can put my future clinical translation toward creating the optimal outcome,” Yu said. “This is a critical step. The donors giving the money to help us do this are not only benefiting patients, they’re also promoting science in general.”