Researchers at the Icahn School of Medicine at Mount Sinai and the Mount Sinai Tisch Cancer Center have discovered a biological pathway that helps explain why some bladder cancers do not respond well to immunotherapy. Their findings, published in Cancer Discovery ( 10.1158/2159-8290.CD-25-1774 ), show that common signs of inflammation in the blood are linked to immune cells inside tumors that block the body's ability to fight cancer.
The work reveals a previously unrecognized link between systemic inflammation in the blood and immune suppression inside tumors. The study was led by Nina Bhardwaj, MD, PhD, Director of Immunotherapy and Ward-Coleman Chair in Cancer Research at the Icahn School of Medicine; Matthew Galsky, MD, Director of Genitourinary Medical Oncology and Deputy Director of the Mount Sinai Tisch Cancer Center; and Diego Chowell, PhD, Assistant Professor of Artificial Intelligence and Human Health, and Immunology and Immunotherapy, at the Icahn School of Medicine.
The study's first co-authors are Michelle A. Tran, PhD, an MD/PhD student at the Icahn School of Medicine at Mount Sinai; and Mount Sinai researchers Byuri Angela Cho, PhD; Sudeh Izadmehr, PhD; and Seung-Keun Yoo, PhD.
Immunotherapy has improved care for many patients with bladder cancer. Still, doctors do not fully understand why some patients respond to treatment while others do not. High levels of C-reactive protein (CRP), an inflammation marker in the blood, have long been linked to worse outcomes, but the biological connection between inflammation in the blood and the tumor itself has remained unclear.
The researchers found that high levels of CRP and another blood inflammation marker, interleukin-6 (IL-6), are linked to a specific group of immune cells inside tumors. These immune cells, called SPP1+ macrophages, can shut down cancer-fighting T cells. When this happens, immunotherapy drugs known as immune checkpoint inhibitors may not work as well.
"Immune checkpoint inhibitors have changed how we treat bladder cancer, but many patients do not have long-lasting responses," said Dr. Bhardwaj, who is also Professor of Medicine (Hematology and Medical Oncology), and Urology, at the Icahn School of Medicine at Mount Sinai. "We found that common blood markers like CRP and IL-6 are not just general signs of inflammation. They reflect a specific immune process inside the tumor that may block treatment."
The Mount Sinai scientists analyzed bladder tumor samples using advanced genetic tools. They built the largest single-cell atlas of bladder tumors to date and combined it with RNA sequencing data from multiple groups of patients treated with immunotherapy.
The researchers found that tumors from patients with high levels of IL-6 in their blood were more likely to contain SPP1+ macrophages. Further analysis revealed that these macrophages suppress T cells in part through IL-6-related signaling pathways. In contrast, the team identified another type of macrophage marked by CXCL9 (Chemokine ligand 9) that helps activate T cells and is linked to stronger immune responses.
"Our study shows that systemic inflammation can provide insight into what is happening inside tumors," said Dr. Chowell. "Inflammatory signals in the blood reflect specific immune programs that suppress T cells and limit the effectiveness of immunotherapy."
By connecting systemic inflammation in the bloodstream with immune dysfunction inside tumors, the study may point to a promising target for future therapies that could block or reprogram these macrophages, restore immune activity, and expand the number of patients who benefit from immunotherapy in bladder cancer and potentially other inflammation-driven cancers.
"For clinicians, these results suggest that commonly used blood tests may provide insight into what is happening inside a patient's tumor before treatment begins," Dr. Galsky said. "This framework may help identify patients who are more likely to have resistance to immunotherapy and support testing new combination treatment strategies."
The findings also provide support for ongoing and future clinical trials studying drugs that target IL-6 signaling and related inflammatory pathways alongside immunotherapy. For patients, the research helps explain why some bladder cancers do not respond well to immunotherapy.
The research team is now continuing to study SPP1+ macrophages to better understand how they suppress the immune system and how future therapies might target or reprogram them. The research was supported by National Institutes of Health R01 and F30 awards.
Full study and complete list of authors: https://aacrjournals.org/cancerdiscovery/article/doi/10.1158/2159-8290.CD-25-1774/774912/A-tumor-promoting-inflammatory-SPP1-macrophage-IL
