Co-first author Jayadev Mavuluri, PhD, St. Jude Department of Pathology, senior co-corresponding author Terrence Geiger, MD, PhD, St. Jude Academic and Biomedical Operations senior vice president and Academic and Biomedical Operations deputy director, Department of Immunology interim chair and Department of Pathology member, co-corresponding author Jiyang Yu, PhD, St. Jude Department of Computational Biology interim chair and co-first author Yogesh Dhungana, St. Jude Graduate School of Biomedical Sciences.
Manipulating the immune system to treat cancer has generated phenomenal responses in some patients, including complete cures, but those responses do not last for everyone. For example, chimeric antigen receptor (CAR) T–cell immunotherapy causes an initial response in 90% of B-cell acute lymphoblastic leukemia (B-ALL) patients. But there is also a 50% chance a patient will experience a difficult-to-treat relapse of their disease after CAR T–cell therapy. St. Jude Children’s Research Hospital scientists have uncovered a reason why — and report a potential way to prevent relapse. The findings were published today in Cancer Discovery, a journal of the American Association for Cancer Research.
The researchers discovered that the G-protein coupled receptor 65 (GPR65) gene is inactive in some tumors, and its reduced activity correlates with resistance to immunotherapy. Chemically compensating for GPR65’s inactivation improved survival and tumor control in laboratory models. The St. Jude researchers made this discovery by looking for ways the tumor interferes with CAR T–cell therapy rather than just how to improve the treatment design.
“We used an integrative computational approach to explore how the tumor suppresses immunotherapy activity in B-ALL, identifying a new potential avenue to design interventions,” said co-corresponding author Jiyang Yu, PhD, St. Jude Department of Computational Biology interim chair. “We compared the gene expression of responders and nonresponders to CAR T–cell treatment and other immunotherapies in clinical trials, retrospectively and in our model systems, uncovering reduced activity of GPR65 in the tumor as the top driver of poor response.”
“In the past, we haven’t had good biomarkers to predict immunotherapy response,” said senior co-corresponding author Terrence Geiger, MD, PhD, St. Jude Academic and Biomedical Operations senior vice president and deputy director of Academic and Biomedical Operations, Department of Immunology interim chair and Department of Pathology member. “We may now have a potential antigen-independent tumor biomarker in GPR65 to identify which tumor will respond well when considering immunotherapy or if other treatments should be considered. Our work also identified a pathway that could potentially be therapeutically targeted to improve immunotherapy.”
Microenvironment suppresses immunotherapy
After identifying GPR65’s importance, the scientists studied how it affected the microenvironment, the soup of chemicals, signals and structures surrounding the tumor. In a mouse model with an intact immune system, removing GPR65 prevented CAR T cells from effectively treating B-ALL.
“GPR65 is a sensor protein, so when it’s not there, the body becomes partly blind to what’s happening around the tumor,” said co-first author Yogesh Dhungana, St. Jude Graduate School of Biomedical Sciences. “We don’t know exactly how, but its decreased activity allows the tumor to go haywire, change its environment and help it thrive.”
One way tumors with low GPR65 modified their microenvironment was by recruiting immune cells called macrophages. Those macrophages sent out signals opposing other immune cells, effectively blocking the local activity of therapeutic T cells.
“We found our GPR65 knockout tumors were recruiting a high percentage of macrophages that turned immunosuppressive,” said co-first author Jayadev Mavuluri, PhD, St. Jude Department of Pathology. “But if we depleted macrophages, we saw the mice treated with CAR T cells survived longer.”
Suppressing the suppressor with a VEGFA inhibitor
There are currently no approved treatment methods to deplete the total macrophages during immunotherapy. Instead, the researchers looked at gene expression to identify new potential therapeutic strategies. They found that when tumors decrease GPR65 expression, their vascular endothelial growth factor A (VEGFA) expression increases. VEGFA is known to attract macrophages and can foster immunosuppressive activity. When treating models with a drug inhibiting VEGFA, they saw a significant increase in CAR T cells’ ability to destroy the tumor. VEGF inhibitors are already commonly used in cancer treatment, easing the path to further investigation and potential future regulatory approval.
“We’ve identified a proof-of-principle potential therapeutic opportunity using the combination of CAR T–cell immunotherapy and an anti-VEGF drug,” Yu said. “We hope this approach will help prolong the effectiveness of the treatment and prevent relapse for patients with B-ALL, but we still need further investigation to find the best method to improve these immunotherapies.”
Authors and funding
The study’s other authors are Lindsay Jones, Sheetal Bhatara, Hao Shi, Xu Yang, SongEun Lim, Noemi Reyes and Hongbo Chi, all of St. Jude.
The study was supported by grants from the National Institutes of Health (R01GM134382 and U01CA264610), The Assisi Foundation of Memphis and ALSAC, the fundraising and awareness organization of St. Jude.
St. Jude Children's Research Hospital
St. Jude Children's Research Hospital is leading the way the world understands, treats and cures childhood cancer, sickle cell disease, and other life-threatening disorders. It is the only National Cancer Institute-designated Comprehensive Cancer Center devoted solely to children. Treatments developed at St. Jude have helped push the overall childhood cancer survival rate from 20% to 80% since the hospital opened more than 60 years ago. St. Jude shares the breakthroughs it makes to help doctors and researchers at local hospitals and cancer centers around the world improve the quality of treatment and care for even more children. To learn more, visit stjude.org, read St. Jude Progress, a digital magazine, and follow St. Jude on social media at @stjuderesearch.