New Technique for Cancer Cells Discovered to Evade Immunotherapies

March 8, 2021
Jill Murphy, Associate Editor

Researchers at Columbia and MIT have created a new technique that can uncover nearly all of the behaviors that cancer cells use to evade immunotherapies, which could lead to the development of more effective treatments.

Researchers at Columbia and MIT have created a new technique that can uncover nearly all of the behaviors that cancer cells use to evade immunotherapies, which could lead to the development of more effective treatments, according to a press release.

The researchers tested the new technique with cancer cells and matching immune cells from melanoma patients and identified previously unknown resistance mechanisms to immune checkpoint inhibitors, which is a widely used class of immunotherapy drugs.

“With drugs called immune checkpoint inhibitors, we’re now getting as close as we have ever been to curing one-third of patients with metastatic melanoma, even at a stage when the disease has spread throughout the body,” said study leader Benjamin Izar, MD, PhD, assistant professor of medicine at Columbia University Vagelos College of Physicians and Surgeonsm, in a press release. “So, the question is, what is happening in the other two-thirds of patients?” Izar says. “What are the mechanisms of intrinsic or adaptive drug resistance?”

In a previous study published in Cell in 2018, Izar and his team identified 250 genes in metastatic melanoma cells that allow them to evade the immunotherapy. This study’s objective was to provide a systematic way to functionally decipher how each of those genes contributes to immunotherapy resistance, according to the press release.

The recent study is the first test of a new tool that combines 2 advanced technologies, CRISPR gene editing technology and single-cell RNA and -protein sequencing. This tool allows researchers to determine the full landscape of how cancer cells can evade the immune system.

Using the CRISPR technology, the research team inactivated the 250 genes to create a mixture of 250 batches of melanoma cells, each with a different mutation. The entire heterogenous population of cancer cells edited by CRISPR were then exposed to T cells, which are the immune cells unleashed by checkpoint inhibitors in patients, according to the study authors.

The cells that resisted being killed by T cells were isolated, and a snapshot of all active processes within these cells was measured using single-cell RNA and protein profiling, which provided a high-resolution molecular map of several gene perturbations resulting in immune escape.

“Our approach is unique in that we study these mechanisms in patient-derived models, and rather than looking at how a gene changes a cell’s phenotype one gene at a time, we were able to study many genes with potential roles in drug resistance in patients in one sweep. It’s the first time that such tools have been used at such a large scale,” Izar said in a press release.

The analysis of approximately a quarter million cells helped identify new mechanisms of resistance to immunotherapy along with mechanisms that were previously known.

“Basically, we recovered the majority of known mechanisms described over the last 10 years, validating that our approach works and giving us confidence that the new findings are important,” Izar said in a press release.

One of the new resistance mechanisms includes a gene called CD58.

“Our data suggest that loss of CD58 in melanoma cells confers immune escape through three potential mechanisms: impairing activation of T cells, reducing the ability of T cells getting into the tumor, and increasing the production of PD-L1,” said study author Johannes C. Melms, MD in a press release. “Because the CD58 gene is not mutated per se but rather just turned off, it raises the possibility that therapies that turn it on could overcome drug resistance in some patients.”

Based on their findings, the researchers plan to develop a way to improve response to immunotherapies. Additionally, future experiments are planned to examine inactive various combinations of cancer cell genes at once.

“In this study, we looked at what happens to cells when only one gene is inactivated,” Melm said in a press release. “But it’s likely that no single gene is sufficient to confer all the types of resistance to immunotherapy that we see in clinical practice.”

REFERENCE

Why some melanoma patients do not respond to immunotherapy. Columbia University Irving Medical Center. https://www.cuimc.columbia.edu/news/why-some-melanoma-patients-do-not-respond-immunotherapy. Published March 1, 2021. Accessed March 3, 2021.