For decades, scientists have explored ways to strengthen the immune system's ability to recognize and destroy tumors, including engineering T cells to seek out specific cancer targets. But some cancers manage to stay one step ahead. They develop a way to conceal the molecular signals, or antigens, that T cells rely on to recognize them in the first place, essentially hiding in plain sight.
Faced with this challenge, researchers at Fred Hutchinson Cancer Center turned to a different strategy, developing T cells that can not only attack cancer but also help make tumors more visible to the immune system.
Merkel cell carcinoma (MCC) is a rare, aggressive skin cancer, with around 80% of cases driven by Merkel cell polyomavirus. The virus produces proteins that can serve as recognizable targets for the immune system, making these tumors promising candidates for T cell-based immunotherapies. Although immune checkpoint inhibitors have improved outcomes for patients with MCC, many tumors eventually develop resistance.
In a new study published in Science Translational Medicine, a research team led by Dr. Aude Chapuis investigated whether genetically engineered T cells could offer another treatment option. The researchers identified a T-cell receptor capable of recognizing a fragment of a viral protein, known as large-T antigen, displayed on the surface of MCC cells. They then equipped patients' own T cells with this receptor, giving them the ability to recognize and attack cancer cells displaying the viral target.
Seven patients with advanced Merkel cell carcinoma who had resisted previous immunotherapy received the engineered T cells, alongside immune checkpoint inhibitors and additional treatments. The engineered cells successfully reached tumors, and tumor regression was observed in two patients. However, most patients experienced continued disease progression, raising an important question: why were the engineered T cells unable to eliminate the cancer?
Analysis of tumor biopsies revealed a major obstacle. Many tumors expressed little or no human leukocyte antigen (HLA), molecules that display fragments of the viral proteins on the cancer cell surface for T cells to recognize. By suppressing HLA expression, cancer cells could effectively conceal their identity, preventing even highly targeted immune cells from recognizing them.
As Dr. Joy Sung, a postdoctoral researcher in the Chapuis Lab, explained, “Successful T-cell therapy depends on both sides of the interaction. We need T cells that can recognize the cancer, but the cancer also needs to remain visible to those T cells."
The patient whose tumors regressed provided another important insight. As the patient’s cancer began to shrink, researchers observed increased HLA expression alongside an influx of naturally occurring T cells that recognized a different viral target. Although the precise events responsible for the delayed response remain unclear, the findings suggested that sufficiently strong local immune activity could restore the cancer's visibility and potentially recruit the patient's own immune defenses.
“These observations raised the possibility that T cells do more than just directly attack tumor cells,” Sung added.
Building on these findings, the researchers redesigned their engineered T cells to improve their effectiveness against tumors with low HLA expression. They introduced an additional coreceptor to help T cells recognize cancer cells displaying fewer viral targets. They also incorporated a synthetic “switch” receptor that converts interactions with CD200, a molecule commonly found on Merkel cell tumors, into signals that stimulate T-cell activity.
When tested in mice bearing human Merkel cell tumors, the redesigned T cells accumulated more effectively within tumors, increased tumor HLA expression, and produced stronger, more sustained control of tumor growth compared with the original engineered cells.
Although these enhanced T cells have yet to be tested in patients, the findings offer a promising strategy for addressing immune evasion in Merkel cell carcinoma and potentially other solid tumors characterized by poor antigen presentation.
Looking ahead, the team aims to improve the durability of these responses by developing T cells that function effectively even when tumors suppress antigen presentation, while also creating conditions that allow the patient’s immune system to recognize and respond to the cancer.
Fred Hutch/University of Washington/Seattle Children’s Cancer Consortium Members Drs. Joshua R. Veatch, Francesco Mazziotta, Evan W. Newell, Heather H. Gustafson, Cecilia C. S. Yeung, David M. Koelle, Shailender Bhatia, Evan T. Hall, Ted Gooley, Philip D. Greenberg, Shannon K. Oda, Paul Nghiem, and Aude G. Chapuis contributed to this research.
The spotlighted research was funded by the National Institutes of Health, BlueBird Bio Inc., Affini-T Therapeutics Inc., the Parker Institute for Cancer Immunotherapy, the Fund for Science and Technology, the Bezos Immunotherapy Fund, the Immunotherapy Integrated Research Center at the FHCC, and the Japan Society for the Promotion of Science.
Asano Y, Veatch JR, Sung C, Tang T, Mazziotta F, Natsuki S, McAfee M, Bakhtiari J, Lee B, Martin L, Rizzi A, Zhang T, Smith CW, Paulson KG, Schmitt TM, Newell EW, Elz AE, Chen DG, Su Y, Gustafson HH, Yeung CCS, Seaton B, Hunter D, Koelle DM, Bhatia S, Hall ET, Voillet V, Cao J, Gooley T, Greenberg PD, Gottardo R, Oda SK, Nghiem P, and AG Chapuis. 2026. Reprogramming engineered autologous T cells to overcome resistance in patients with Merkel cell carcinoma. Science Translational Medicine. DOI: 10.1126/scitranslmed.aea8773
Science Spotlight writer Thamiya Vasanthakumar is a postdoctoral research fellow in the Campbell Lab at Fred Hutch. As a structural biologist, she uses cryogenic electron microscopy (cryoEM) to visualize the molecular structures of receptors found on the surface of immune cells.