Scientists at the Icahn School of Medicine at Mount Sinai have identified an important immune response that helps explain why some cancer patients benefit from immunotherapy while others do not.
In a study published in the January 27 online issue of Nature Medicine (DOI 10.1038/s41591-025-04177-6), the researchers found that antibody-producing immune cells called IgG1 plasma cells play a key role in helping patients respond to PD-1 immune checkpoint inhibitors.
PD-1 immune checkpoint inhibitors are a type of immunotherapy that helps the immune system recognize and attack cancer. They have transformed cancer care and are now a backbone of treatment across many tumor types. But not all patients experience durable benefit, and the biological reasons behind this variability are not completely understood.
"While PD-1 therapies are often described as working exclusively through T cells, our data show that antibody-producing plasma cells (specifically those making IgG1 antibodies) are a critical part of the picture," said Sacha Gnjatic, PhD , Professor of Immunology and Immunotherapy at the Mount Sinai Tisch Cancer Center and the Icahn School of Medicine at Mount Sinai, and corresponding author of the study. "These cells appear to help coordinate a more effective, tumor-specific immune response."
The research team initially studied tumor and blood samples from 38 patients with liver cancer who received PD-1 therapy before surgery. Patients were considered responders if more than half of their tumor tissue was destroyed by treatment.
Using advanced transcriptomic, proteomic, and computational tools to study the immune cells in detail, the researchers found that tumors from responders contained more IgG1 plasma cells, especially during treatment. These cells showed signs of clonal expansion, meaning they were copies of the same immune cells reacting to specific targets in the tumor. These clones were found circulating between tumor and lymph nodes, and shared with memory B cells, which are precursors to plasma cells.
Importantly, rather than relying solely on new B cells generated from scratch, PD-1 therapy appeared to expand (to divide, so that they are more prevalent) B cell clones that were already present before treatment, and these expanded cells were linked to better outcomes.
Blood samples from responders also contained IgG1 antibodies that recognized tumor-specific proteins, including cancer-testis antigens such as NY-ESO-1. These proteins are found mostly in cancer cells and not in healthy tissue. Patients with these antibodies also showed stronger tumor-targeting T cell activity, pointing to a coordinated and tumor-specific immune response.
To confirm their findings, the researchers analyzed data from seven additional clinical trials totaling more than 500 patients, including independent new datasets and previously published studies with PD-1 blockade across different diseases. These were studied with genetic sequencing, spatial tumor analysis from other patients, and survival data from more than 1,500 additional patients in public databases. These results showed that IgG1 plasma cells were linked to better outcomes only in patients treated with immunotherapy, not in those receiving standard treatments alone.
"Validating high-throughput findings using publicly available datasets offers the strongest evidence for identifying robust and reproducible markers of clinical response. This approach represents the true path to scientific progress as we develop and apply innovative algorithms," said Edgar Gonzalez-Kozlova, PhD , Assistant Professor of Immunology and Immunotherapy at the Mount Sinai Tisch Cancer Center and the Icahn School of Medicine at Mount Sinai.
Together, the findings show that PD-1 therapy triggers a coordinated immune response in which antibodies and T cells work together to fight cancer.
The study suggests that IgG1 plasma cells could become a biomarker to help predict which patients are most likely to benefit from immunotherapy. It also opens the door to new treatment strategies that boost tumor-specific antibody responses, such as cancer vaccines used alongside PD-1 therapy.
"Our long-term hope is that understanding the antibody landscape within tumors could help guide treatment decisions and reduce unnecessary exposure to therapies that may be unlikely to work for certain patients," said Dr. Gnjatic.
Next, the research team plans to study this immune response in other cancers, including blood cancers such as multiple myeloma, and to better understand how antibodies in the blood are linked to plasma cells inside tumors.
The paper is titled "Humoral IgG1 responses to tumor antigens underpin clinical outcomes in immune checkpoint blockade.
The study was conducted by a large multidisciplinary team at the Icahn School of Medicine at Mount Sinai, including experts in oncology, pathology, immunology, and computational biology and its Human Immune Monitoring Center (HIMC) . Key investigators included Thomas Marron, MD, PhD; Miriam Merad, MD, PhD; and Seunghee Kim-Schulze, PhD, with collaboration from Regeneron, which provided study drugs and assay support for a subset of patients. The analytical team was led by Edgar Gonzalez-Kozlova, PhD; Robert Sweeney, MD, MPhil; Kevin Tuballes, MD, and Igor Figueiredo,MSc, under Dr. Gnjatic's supervision.
Additional collaborators included researchers from the National Cancer Center in Japan. Funding was provided primarily through grants from the National Cancer Institute, with supplemental seed funding for advanced immune profiling.
For a full list of authors and disclosures, please see the paper here: https://www.nature.com/articles/s41591-025-04177-6
