A Mount Sinai study finds that a specific type of antibody-producing immune cell, the IgG1 plasma cell, helps determine which patients benefit from PD-1 cancer immunotherapy. The work could lead to better prediction of treatment response and new combination strategies like cancer vaccines.
Some of the most powerful cancer drugs today can unleash the immune system against tumors, yet many patients never see lasting benefit. A new study from the Icahn School of Medicine at Mount Sinai points to a surprising player that may help explain why: antibody-producing immune cells called IgG1 plasma cells.
The research, published in Nature Medicine, suggests that these cells and the antibodies they make help determine which patients respond to PD-1 immune checkpoint inhibitors, a widely used class of immunotherapy drugs.
PD-1 inhibitors work by taking the brakes off immune cells so they can attack cancer. They are now standard treatment for many tumor types, from lung and liver cancers to melanoma. But only a fraction of patients experience strong, durable responses, and doctors still lack reliable ways to predict who will benefit.
The research team focused on a part of the immune system that has received less attention in this context: B cells and the plasma cells they become when they start producing antibodies. In particular, they zeroed in on plasma cells that make a subtype of antibody known as IgG1.
Corresponding author Sacha Gnjatic, a professor of immunology and immunotherapy at the Mount Sinai Tisch Cancer Center and the Icahn School of Medicine at Mount Sinai, noted that challenges a common assumption about how PD-1 drugs work.
“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,” Gnjatic said in a news release. “These cells appear to help coordinate a more effective, tumor-specific immune response.”
To uncover that role, the team first analyzed 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 the treatment.
Using advanced tools that read out which genes and proteins immune cells are using, and computational methods to map how those cells are related, the researchers compared responders and nonresponders in detail.
They found that tumors from patients who responded to PD-1 therapy contained more IgG1 plasma cells, especially during treatment. These cells showed signs of clonal expansion, meaning many of them were copies of the same original cell reacting to specific targets in the tumor.
Those clones were not confined to a single site. The team detected related cells circulating between tumors and nearby lymph nodes and found that they were shared with memory B cells, which can later develop into plasma cells. That pattern suggested an ongoing, coordinated immune reaction against tumor-specific targets.
The researchers also discovered that PD-1 therapy did not simply generate new B cells from scratch. Instead, it appeared to expand B cell clones that were already present before treatment. Patients in whom these preexisting clones expanded more robustly tended to have better outcomes.
Blood samples from responders offered another clue. These patients had IgG1 antibodies that recognized tumor-specific proteins, including so-called cancer-testis antigens such as NY-ESO-1. These proteins are typically found in cancer cells but not in most healthy tissues, making them attractive targets for immune attack.
Patients with these tumor-recognizing antibodies also showed stronger T cell activity directed at the tumor. Together, the findings point to a coordinated response in which antibodies and T cells reinforce each other to fight cancer.
To test whether this pattern held up beyond a single group of liver cancer patients, the team turned to a much larger set of data. They examined results from seven additional clinical trials that together included more than 500 patients treated with PD-1 blockade across different diseases. They also drew on genetic sequencing, spatial analysis of tumors from other patients, and survival data from more than 1,500 patients in public databases.
Across these independent datasets, IgG1 plasma cells were consistently linked to better outcomes in patients who received immunotherapy. Importantly, that association did not appear in patients treated with standard therapies alone, suggesting that these cells are specifically tied to how checkpoint inhibitors work.
First author Edgar Gonzalez-Kozlova, an assistant professor of immunology and immunotherapy at the Mount Sinai Tisch Cancer Center and the Icahn School of Medicine at Mount Sinai, emphasized the importance of this broad validation.
“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,” Gonzalez-Kozlova said in the news release.
Taken together, the results highlight a humoral immune response — the arm of immunity driven by antibodies — as a key partner to T cells in successful PD-1 therapy. Rather than acting alone, T cells may rely on antibody-producing cells to help flag tumor targets, shape the immune environment, and sustain the attack.
Clinically, the work points toward several potential applications.
First, IgG1 plasma cells could serve as a biomarker to help predict which patients are most likely to benefit from PD-1 inhibitors. Measuring these cells or the antibodies they produce in tumors or blood might one day help oncologists decide who should receive checkpoint blockade, who might need additional therapies, and who might be spared from side effects if the drugs are unlikely to work.
“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,” Gnjatic added.
Second, the findings open the door to new combination strategies. If tumor-specific antibodies and IgG1 plasma cells help drive response, then treatments that boost those responses — such as cancer vaccines or therapies that stimulate B cells — could potentially be paired with PD-1 inhibitors to improve outcomes.
The study also raises basic scientific questions. For example, how exactly do IgG1 plasma cells and their antibodies interact with T cells and other immune cells inside tumors? Why do some patients have preexisting B cell clones that can be expanded by PD-1 therapy while others do not? And can those clones be induced or strengthened before treatment begins?
To begin answering those questions, the Mount Sinai team plans to study similar immune responses in other cancers, including blood cancers such as multiple myeloma. They also aim to better understand how antibodies circulating in the blood are linked to plasma cells residing inside tumors.
The work drew on a large, multidisciplinary team at Mount Sinai, including experts in oncology, pathology, immunology, computational biology and its Human Immune Monitoring Center, with collaborators in Japan.
As immunotherapy continues to reshape cancer care, studies like this one highlight that the immune system’s response to cancer is not driven by a single type of cell. Instead, it is a complex network of T cells, B cells, antibodies and other players — and understanding how they work together may be the key to helping more patients benefit from these powerful treatments.
Source: Mount Sinai