Reframing the Challenge: What Makes a Good Target?
Despite notable advances in diagnostics and therapeutics, metastatic breast cancer remains a major clinical challenge. Durable responses are rare, and recurrence is common. One persistent obstacle is identifying molecular targets that are:
- Functionally relevant to the metastatic process,
- Selectively expressed in tumor cells or permissive environments, and
- Accessible to therapeutic modulation.
Traditional transcriptomic studies, based on bulk tumor tissue, often blur the signals of rare or transiently expressed genes [1]. In this context, many potentially meaningful targets have remained undetected.
Single-Cell RNA-Seq: A Clearer Lens
To overcome this limitation, we applied single-cell RNA sequencing (scRNA-seq) to tumor samples from patients with advanced, treatment-resistant breast cancer. This approach allowed us to resolve gene expression at cellular resolution across epithelial tumor cells, immune infiltrates, and stromal components [2].
Among the unexpected findings was a consistent, elevated expression of CD83 in a subset of tumor epithelial cells. This was striking given that CD83 is classically described as an activation marker for dendritic cells and B cells [3]. Its emergence in epithelial cells prompted deeper investigation.
CD83 as a Functional Oncogenic Player?
Beyond expression, CD83-high tumor cells exhibited unique transcriptional profiles:
- Enrichment in immune escape–related pathways,
- Upregulation of adhesion and migration genes, and
- A correlation with worse overall survival in public patient datasets [4].
These features suggest CD83 may be more than a passive marker, it may play an active role in shaping the metastatic phenotype. Moreover, its extracellular positioning makes it an attractive target for antibody-based approaches, including monoclonal antibodies, CAR-T therapies, or antibody-drug conjugates [5].
Why Has CD83 Been Overlooked?
There are several reasons CD83 may have escaped attention:
- Its known role in immune cells likely caused it to be excluded from oncology target screens [3].
- Bulk RNA-seq likely diluted or masked its expression in rare tumor cell subtypes [1].
- It may only become relevant in late-stage or treatment-resistant contexts, which are less frequently sampled in high-resolution studies [6].
This highlights how even well-studied molecules can take on new roles when observed under the right conditions.
Implications for Discovery and Therapeutics
This finding reinforces several broader themes:
- Single-cell technologies are not just academic tools, they are critical for uncovering disease complexity that bulk approaches miss [2,7].
- Immune-related receptors may play unexpected roles in epithelial cancers and deserve reevaluation [4,8].
- Therapeutic targeting strategies should consider not just oncogenes and signaling pathways, but also modulators of the tumor-immune interface [9].
In an era of precision oncology, expanding the scope of what we consider “targetable” could unlock much-needed therapeutic advances.
Final Thoughts
Our work on CD83 is ongoing, but the early data is compelling. It is a vivid example of how computational biology and single-cell transcriptomics can reframe existing molecules in a new therapeutic light.
Sometimes, the next breakthrough isn’t a brand-new discovery, it’s a familiar receptor, hiding in plain sight.
References
- Wang, Y. et al. (2019). Bulk transcriptomics conceals tumor heterogeneity: limitations and opportunities. Nature Reviews Genetics, 20, 133–145.
- Wagner, J. et al. (2019). A single-cell atlas of the tumor and immune ecosystem of human breast cancer. Cell, 177(5), 1330–1345.e18.
- Prechtel, A. T. et al. (2007). CD83 expression is a hallmark of dendritic cell maturation. International Journal of Clinical Pharmacology and Therapeutics, 45(12), 735–740.
- The Cancer Genome Atlas (TCGA). (2012). Comprehensive molecular portraits of human breast tumors. Nature, 490, 61–70.
- Scott, A. M., Wolchok, J. D., & Old, L. J. (2012). Antibody therapy of cancer. Nature Reviews Cancer, 12, 278–287.
- Bos, P. D. et al. (2009). Genes that mediate breast cancer metastasis to the brain. Nature, 459, 1005–1009.
- Tirosh, I. et al. (2016). Dissecting the multicellular ecosystem of metastatic melanoma by single-cell RNA-seq. Science, 352(6282), 189–196.
- Schiavoni, G., Mattei, F., & Gabriele, L. (2013). Type I interferons as stimulators of DC-mediated cross-priming: impact on anti-tumor response. Frontiers in Immunology, 4, 483.
- Chen, D. S., & Mellman, I. (2017). Elements of cancer immunity and the cancer–immune set point. Nature, 541, 321–330.
About the Author
Dr. Hazem Mustafa is the Co-Founder and CEO of Bioada, a biotechnology company advancing precision medicine through AI-driven, multi-omics discovery. His work spans oncology, neurology, and rare diseases, with a focus on identifying novel biomarkers and therapeutic targets through cutting-edge computational biology.