A new UCLA Health Jonsson Comprehensive Cancer Center study suggests that the way immune cells are organized inside melanoma tumors may help researchers better understand which patients will benefit from combination immunotherapy after standard anti-PD-1 treatment stops working — and which may not.
The findings , published in Cancer Discovery, a journal of the American Association for Cancer Research, show that patients whose tumors contained active networks of cancer-killing T cells were more likely to benefit from treatment, while those with dense clusters of plasma cells were far less likely to benefit.
Why it matters
Anti-PD-1 drugs have become the backbone of treatment for advanced melanoma by helping the immune system recognize and attack cancer cells. But many tumors eventually stop responding or never respond at all. When that happens, doctors often turn to another type of immunotherapy, anti-CTLA-4. Even then, only about 30% of patients see meaningful benefit. Researchers have long known that tumors with more immune activity tend to respond better. What has been less clear is why some tumors remain resistant, even when a second immune drug is added, and whether there is a way to identify those cases earlier.
What the study did
To address this question, researchers analyzed tumor biopsies from patients enrolled in the SWOG S1616 clinical trial. All had melanoma that had already progressed on anti-PD-1 therapy. Patients were randomly assigned to receive either a combination of two immunotherapies — ipilimumab (which targets CTLA-4) and nivolumab (which targets PD-1) — or ipilimumab alone. Tumor biopsies were taken before treatment and again about a month later. Working with collaborators at the Parker Institute for Cancer Immunotherapy and industry partners, the team combined genetic sequencing with high-resolution imaging to map not just which genes were active in the tumors, but where different immune and cancer cells were physically located.
What they found
The researchers found that tumor genetics alone did not explain which patients responded to treatment. Instead, the most important differences were seen in the tumor's immune environment.
In patients who responded to combination therapy, CD8 T cells, the immune system's primary cancer-killing cells, were able to enter the tumor and cluster closely around melanoma cells. These tumors also showed evidence of active immune signaling, with different CD8 T cell populations present, including cells actively dividing near tumor cells. As tumors began to shrink, additional immune cells such as regulatory T cells and monocytes, also appeared in the tumor microenvironment.
Rather than acting in isolation, immune and cancer cells formed organized patterns of interaction, often referred to as cellular neighborhoods, where different cell types work together within specific regions of the tumor. In contrast, tumors that did not respond to treatment often contained dense clusters of plasma cells. These plasma cell-rich regions were associated with reduced T cell activity and continued tumor growth, suggesting they may be linked to a tumor environment that is less able to support an effective immune attack.
The study also highlights why the physical location of immune cells inside a tumor is so important. The researchers found that T cells in responding tumors were positioned near blood vessels and other supportive immune cells, allowing them to move into the tumor and coordinate an effective attack.
"The T cells need to directly see the cancer cells to kill them, but they also need to be able to move around and get the correct signals to tell them to keep going or keep killing," said Dr. Katie Campbell , adjunct assistant professor of medicine at the David Geffen School of Medicine at UCLA and first author of the study. "If they can't get into the tumor through blood vessels, or don't get these signals because the right types of immune cells aren't there, the patient isn't going to respond to the therapy."
What this means for patients
The findings suggest it may eventually be possible to use tumor structure, not just genetics, to help guide treatment decisions in melanoma, identifying patients most likely to benefit from combination immunotherapy and those who may need a different treatment approach sooner.
What's next
Researchers say the next step is figuring out how to reshape the tumor environment in patients whose cancers resist immune attack, and how to better combine immunotherapy with treatments such as targeted therapy, chemotherapy or radiation to improve response rates.
About the researchers
The study's senior author is Dr. Antoni Ribas , professor of medicine at the David Geffen School of Medicine at UCLA and director of the UCLA Health Jonsson Comprehensive Cancer Center's Tumor Immunology & Immunotherapy Program. Ribas is also the director of the PICI Center at UCLA and a member of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research. Other UCLA researchers are Daniel Chen, Zaid Bustami1, Nataly Al Deen, Egmidio Medina, Cynthia Gonzalez, Ivan Garcilazo, Ignacio Baselga-Carretero, Agustin Vega-Crespo, Jia Chen, Cadence Chang, Alan Zelin, Sai Chelluri, Bartosz Chmielowski and Philip Scumpia.
Funding
The work was funded in part by Stand Up To Cancer (SU2C) Catalyst–Bristol Myers Squibb–American Association for Cancer Research, the Parker Institute for Cancer Immunotherapy, the National Institutes of Health, an Agilent Thought Leader Award, the Ressler Family Fund and philanthropic support.
