Tumors generate their own temporary subcellular structures to evade immunotherapy

Scientists have shown how tumor cells evade immunotherapy by generating their own temporary intracellular cellular structures. In this structure, the inner cells remain intact and can revert to single tumor cells.

These findings were published today e-life, offers a new theory for how tumor cells evade destruction by the immune system. They may also inform the development of therapies that combine immunotherapy with timed inhibition of relevant signaling pathways in tumor cells.

“Cancer immunotherapy uses the body’s immune system to fight cancer. They will only shrink in size and these recurrent tumors may become resistant to immunotherapy treatment.” First author Amit Gutwillig was a PhD student at the Carmi Lab at Tel Aviv University in Israel at the time the study was conducted and is now a Senior Fellow at his Nucleai in Tel Aviv.

To identify how tumors recur after immunotherapy, Carmi and team began by comparing the genome-wide gene sequences of primary and recurrent tumors from the same patient. Their analysis suggests that recurrent tumors do not change dramatically after immunotherapy.

The team then studied this process in breast cancer, melanoma, using a mouse model in which immunotherapy-resistant tumors have relapsed. They administered cells from the treated tumors to mice and allowed these cells to reach a palpable size. I found one, but the recurrence was quicker.

To better characterize surviving tumor cells in mice after immunotherapy, researchers isolated and studied live tumor cells.they are most cells T cells – a type of immune cell that targets foreign particles – by organizing into temporary tissues. was configured. The inner cells of the strata were dense and appeared to be compressed within another cell.

To show that the results were not due to melanoma cell isolation, the team also analyzed tumors with fluorescently labeled nuclei and membranes. They found that intracellular cytogenesis was more prevalent in tumors treated with immunotherapy, especially at sites associated with tumor cell death. Further analysis showed that approximately half of the tumor cells that survived immunotherapy were arranged in cell-in-cell structures. Over time, these cells reverted to a single-cell state with structural features similar to the parental cell line.

The team next tested whether this phenomenon occurs in human cancers. To do this, they incubated tumor cell lines with preactivated T cells from healthy donors. We found that most are organized into subcellular cellular structures. When he watched his T cells interact with tumor cells for three days, he found that these structures were dynamic, with individual tumor cells constantly forming and spreading out of them.

Finally, we tested the clinical relevance of this finding by analyzing cancer tissue from multiple organs in four stage 4 melanoma patients. These patients had undergone surgical resection of primary and metastatic lymph nodes, i.e. lymph nodes that had metastasized from the primary tumor. The researchers found that in all four patients intracellular cytoplasia was highly enriched in her T-cell zone of the draining lymph nodes, but not in the primary tumor. Moreover, in patients with untreated recurrent melanoma, cells in primary tumors were mostly single-celled, whereas recurrent tumors were enriched for intracellular cytogenesis.

This previously unknown mechanism of tumor resistance highlights the current limitations of immunotherapy. Over the past decade, many clinical studies have used immunotherapy followed by chemotherapy. However, our findings suggest that timed inhibition of relevant signaling pathways should be performed in parallel with immunotherapy to prevent tumors from becoming refractory to subsequent therapy.”

Yaron Karumi Ssenior author, Chief Scientist, Department of Pathology, Sackler School of Medicine, Tel Aviv University