Cell-in-Cell Formations Help Tumors Evade Immunotherapy

3D image showing immune cells attacking cancer cells in immunotherapy
Photo credit: La Jolla Institute of Immunology

New research from researchers at Tel Aviv University describes how tumor cells form temporary cell-in-cell formations to evade immunotherapy. Their results, published in eLifemay lead to the development of treatments that combine immunotherapy with inhibition of signaling pathways in tumor cells.

“Despite the remarkable success of cancer immunotherapies, the majority of patients will experience only a partial response, followed by relapse of resistant tumors,” the researchers wrote. “While treatment resistance has often been attributed to clonal selection and immune editing, comparisons of paired primary and relapsed tumors in melanoma and breast cancer indicate that they share the majority of clones.”

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“Cancer immunotherapy uses the body’s immune system to fight cancer. Despite the remarkable success, in the majority of patients receiving immunotherapy, tumors will only temporarily shrink before returning, and these relapsed tumors will likely be resistant to immunotherapy treatment,” said first author Amit Gutwill, who was a graduate student at Carmi Lab , Tel Aviv University, at the time the study was conducted, and is now a Senior Researcher at Nucleai.

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Using mouse models and human clinical specimens, researchers showed that tumor cells evade immunotherapy by generating unique transient cell-within-cell structures that are resistant to T-cell killing and chemotherapy. While the outer cells in this cell-in-cell formation are often killed by reactive T cells, the inner cells remain intact and multiply into individual tumor cells when there are no more T cells.

The team also analyzed tumors with fluorescently labeled cell nuclei and membranes. They found that cell-in-cell formation was more common in tumors treated with immunotherapy, particularly at sites that have been associated with tumor cell death.

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“This previously unknown mechanism of tumor resistance highlights a current limitation of immunotherapy,” said senior author Yaron Carmi, PhD, principal investigator in the Department of Pathology, Sackler School of Medicine, Tel Aviv University. “Over the past decade, many clinical trials have used immunotherapy followed by chemotherapy. However, our results suggest that timed inhibition of relevant signaling pathways must occur alongside immunotherapy to prevent the tumor from becoming resistant to subsequent treatments.”

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