Hybrid Tumor-Immune Cells Predict Shorter Survival in Advanced Breast Cancer

Weill Cornell Medicine

Among the cells floating in a cancer patient's bloodstream, there are the usual suspects: circulating tumor cells that broke free from the primary mass, and immune cells patrolling for threats. But a study published in Science Translational Medicine by researchers at Weill Cornell Medicine and NewYork-Presbyterian draws attention to something stranger: cells that appear to be both at once.

These dual-positive (DP) cells carry molecular markers of both tumor cells and immune cells, specifically macrophages, a type of white blood cell. They are thought to arise from rare fusion events between cancer cells and macrophages, creating hybrids with properties of both parents. And in advanced breast cancer, their presence in the blood is associated with significantly shorter survival.

Found in nearly half of patients

The research team, led by senior author Massimo Cristofanilli, analyzed blood samples from 340 women with advanced breast cancer. They detected at least one dual-positive cell in 152 of these women, a rate of 44.7%. DP cells tended to be less numerous than ordinary circulating tumor cells, but their clinical significance was disproportionate.

Patients with three or more detected DP cells had a median survival of 23.5 months, compared to 33.6 months for patients with fewer than three. That ten-month difference was validated in a separate group of 51 additional patients at NewYork-Presbyterian/Weill Cornell Medical Center.

Triple-negative breast cancer bears the brunt

When the researchers broke the results down by breast cancer subtype, the survival risk associated with DP cells was concentrated primarily in triple-negative breast cancer, the subtype defined by the absence of estrogen, progesterone, and HER2 receptors. Triple-negative breast cancer already has the fewest targeted treatment options; the finding that DP cells are particularly relevant in this subtype adds another layer of complexity to an already difficult clinical picture.

Evidence for the fusion hypothesis

Several lines of evidence support the idea that DP cells are genuine tumor-macrophage hybrids rather than artifacts of the detection method. About 60% of analyzed DP cells carried CD14, a standard macrophage marker. The team could only detect DP cells in mouse models of breast cancer when the mice had intact immune systems, suggesting that functional macrophages are required for DP cell formation. And roughly 29% of patient DP cells showed copy number alterations, the kind of genetic abnormalities commonly found in tumors.

Ordinary circulating tumor cells were more likely to show such genetic changes, but DP cells demonstrated a capability that may matter more than genetic purity: in animal models, they could seed metastases. If confirmed in human disease, this would mean that DP cells are not just bystanders or laboratory curiosities but active participants in cancer spread.

A different biology requires different treatment

Current cancer therapies target the molecular features of conventional cancer cells: their growth signals, surface receptors, and metabolic dependencies. DP cells, by inheriting properties from both tumor and immune lineages, may evade these approaches entirely. A cell that expresses macrophage markers might, for instance, avoid immune surveillance by mimicking a normal immune cell, while its tumor-derived genes drive proliferation and metastatic behavior.

Cristofanilli noted that understanding DP cell biology better is a prerequisite for targeting them effectively. The team is currently conducting a comprehensive analysis of DP cells' gene expression patterns to better define their cellular origins and identify potential therapeutic vulnerabilities.

Limitations of the current evidence

The study is observational and cannot establish whether DP cells directly cause worse outcomes or are simply markers of more aggressive disease. Patients with more DP cells may have cancers that are inherently more advanced or biologically aggressive for reasons unrelated to the DP cells themselves.

The metastatic capability of DP cells was demonstrated in mouse models, not in human patients. Whether human DP cells seed metastases with the same efficiency, and whether this process can be interrupted therapeutically, remains unknown.

The initial cohort was assembled at Northwestern University before Cristofanilli moved to Weill Cornell, which means the two patient groups were collected at different institutions over different time periods. While the validation cohort confirmed the survival association, larger prospective studies with standardized collection and analysis protocols would strengthen the conclusions.

The detection threshold of three DP cells as a prognostic cutoff was derived from this dataset and has not been independently validated in external cohorts. The clinical utility of DP cell counts as a biomarker will depend on standardization of detection methods and confirmation of the threshold across diverse patient populations.

Still, the study opens a line of investigation that has received little attention in breast cancer. If DP cells represent a biologically distinct population with unique contributions to metastasis, then ignoring them means treating only part of the disease.