Research Signal – Source date 2026-01-03
A small biopsy can tell doctors what a tumor looks like under a microscope. A harder question is whether a piece of that tumor can reveal how its immune cells might react to immunotherapy. Researchers tested a laboratory approach that exposes living tumor fragments to a control and then an immune checkpoint drug in the same culture well, measuring changes in immune-related proteins along the way.
The study showed that fragments from diagnostic biopsies could remain viable and produce different cytokine patterns after drug exposure. That is a useful demonstration of a test’s laboratory operation. It is not yet evidence that the test can reliably predict whether immunotherapy will help an individual patient.
The challenge starts with a small, uneven sample
Immune checkpoint inhibitors can produce durable responses, but many patients do not benefit. Existing biomarkers—including PD-L1 expression, mismatch repair deficiency or high microsatellite instability, and tumor mutational burden—help identify some patients, yet they do not predict every response. Because these drugs can also cause serious immune-related side effects, researchers are looking for ways to measure how a patient’s own tumor tissue responds.
One approach is to keep pieces of a tumor alive outside the body and expose them to a drug. Unlike a test of isolated cells, live tissue fragments can retain tumor cells, immune cells, and other parts of the local environment. That context matters when the question concerns an immune response inside a tumor.
But tumors are not uniform. Immune cells and viable tumor tissue may be distributed unevenly, so two pieces cut from the same tumor can differ. In a conventional test, one set of fragments goes into control wells and another into drug-treated wells. If those sets happen to contain different mixes of cells, a difference between wells could reflect the tissue sampled as much as the drug.
The problem is sharper with a core needle biopsy, a narrow sample used to diagnose many people with advanced cancer who are not having surgery. There may be too little tissue to divide into enough control and treatment wells, with replicates, to account for that variation. In the study, the researchers found greater variability in drug-associated cytokine measurements from biopsy fragments than from larger surgical specimens using a cross-well comparison.
The same well provides both measurements
The researchers’ alternative was to give the same fragments a control phase followed by a drug phase in the same well. They first measured cytokine accumulation after a control treatment, then added an immune checkpoint inhibitor and measured the accumulation rate again. A change in the rate between phases served as the readout of the tissue’s response.
This paired sequence uses the same collection of fragments for both measurements, reducing the amount of tissue needed compared with a cross-well design. It also avoids treating the contents of one well as a perfect match for the contents of another. The comparison is still a measurement from sampled tissue, but the two phases share that tissue’s particular mix of cells.
The team first compared sequential treatment with separate-well measurements in tumor resections. In six tumors tested with a T-cell stimulation control, the direction of the IFNγ response agreed between approaches in five, and the CXCL10 response agreed in all six. The size of the measured change varied. These experiments supported the method as a way to track cytokine production over time; they did not establish how accurately it forecasts a patient’s clinical outcome.
For the biopsy experiments, fragments received a control treatment and then a checkpoint drug. The drugs differed across the lung, gastrointestinal, and kidney cancer samples. Among biopsies from an initial group of 16 patients, some showed increased rates of IFNγ and CXCL10 accumulation during the drug phase, while others showed little change in those measurements. The patterns varied from specimen to specimen.
Living tissue kept important features, with changes over time
A functional test depends on more than detecting a molecule. The tissue has to remain sufficiently intact for its response to mean something. The researchers assessed fragment viability and examined tissue structure and cell composition during culture.
Across the examined specimens, histological features such as tumor cells, lymphocytes, fibroblasts, and collagen remained visible. Biopsy fragments also retained components including T cells, macrophages, tumor cells, and fibroblasts. T cells could still respond to stimulation in culture, allowing the researchers to measure cytokine changes after treatment.
Preservation was not perfect or absolute. In resection fragments, total cell counts and CD4-positive cell counts fell over 48 hours, and CD8-positive cell counts showed a downward trend. The CD4-to-CD8 ratio remained stable in the examined tumors, and the proportion of CD8-positive cells was maintained in most of them. Biopsy fragments showed maintained viability in the reported assessments, while histology supported retention of major tissue features over the culture period.
These checks help interpret the laboratory measurements: the fragments were not simply inert pieces of tissue, and their immune environment retained important features. They do not remove every source of uncertainty. A sample with substantial dead tissue could appear unresponsive, and a biopsy without tumor tissue could also produce a misleading result. The researchers discussed viability assessment and histological review as ways to identify such problems.
Biomarker findings and biopsy findings answer different questions
The study also found an association in tumor resection specimens: samples positive for PD-L1 or for mismatch repair deficiency or high microsatellite instability were enriched for cytokine upregulation after checkpoint inhibitor exposure. IFNγ and CXCL10 increases were among the immune-related changes associated with biomarker-positive samples.
That result came from the resection analysis. It should not be folded into the separate observation that biopsy response profiles varied. The resection finding links established biomarker status with cytokine changes in those specimens; the biopsy experiments show that the same-well method could detect differing laboratory responses in a small initial group. Neither result, by itself, measures predictive accuracy for future treatment outcomes.
One patient offered a limited clinical comparison. A lung cancer biopsy showed increased IFNγ and CXCL10 accumulation during the laboratory drug phase. The patient later had a 37% reduction in the measured diameter of the biopsied lesion and a partial response after receiving pembrolizumab together with chemotherapy. Because the treatments were combined, the tumor shrinkage cannot be attributed to immunotherapy alone. A single case also cannot validate the assay as a predictor.
A core cannot stand in for every part of a cancer
Even a well-preserved biopsy is a sample from one location. A core may not reflect other regions of the same tumor, and samples are not always collected from multiple lesions. A laboratory result from one biopsy therefore cannot establish how every tumor site in a patient might respond. A lack of cytokine increase in the sampled tissue also cannot reliably rule out benefit elsewhere or under different conditions.
The researchers described ongoing clinical studies intended to compare ex vivo cytokine responses with patient outcomes. That comparison is the necessary next step for learning whether the assay predicts treatment response, and how consistently it does so. The early biopsy experiments establish that the approach can be carried out with limited diagnostic tissue and can produce measurable, varied responses; they do not settle how those measurements should guide care.
What a small biopsy could change in cancer care
If larger clinical studies show that biopsy results reliably track treatment outcomes, a functional test could eventually help clinicians estimate whether a checkpoint inhibitor is likely to benefit a particular patient using tissue already collected for diagnosis. That could make treatment selection more individualized and potentially reduce exposure to a drug that is unlikely to help. Reaching that point depends on showing that laboratory responses correspond to clinical outcomes across many patients, while accounting for sample quality and the fact that one core may not represent the whole cancer.
Key Sources
- Primary source: A live tumor fragment platform to assess immunotherapy response in core needle biopsies while addressing challenges of tumor heterogeneity.
DOI or Journal Page · Clinical Trial · 2026-01-03
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