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Immunotherapy Resistance in Melanoma Linked to Gene Expression Program

NEW YORK (GenomeWeb) – Researchers have teased out a gene expression program that is associated with resistance to immunotherapy in melanoma. Inhibiting this program could improve treatment response.

While immunotherapies like immune checkpoint inhibitors have led to sometimes-dramatic responses in a portion of cancer patients, others don't respond to the treatment.

A team led by researchers at the Broad Institute performed single-cell RNA sequencing on 33 melanoma tumors, about half of which were treatment resistant. As the investigators reported today in Cell, they uncovered a pattern of gene expression associated with treatment resistance. This expression program could also predict treatment response and, when inhibited in mice in conjunction with treatment, improve that response. 

"Our team has mapped out a high­resolution landscape of immunotherapy­resistant melanoma," co-senior author Aviv Regev, director of the Klarman Cell Observatory at the Broad and professor of biology at MIT, said in a statement. "We've discovered a gene expression program that can help predict resistance to immunotherapy before treatment even begins, and a potential way to reverse this program in order to delay or counter that resistance."

To uncover this gene expression program of so-called "cold" tumors — those with low levels of T cell infiltration, a hallmark of immunotherapy resistance — the researchers combined the single-cell RNA-seq data they generated from 33 human melanoma samples with 473 bulk tumor profiles from The Cancer Genome Atlas. Using the scRNA-seq profiles, they distinguished signatures of various cell types, including T cells and malignant cells.

They used those T cell signatures to determine T cell infiltration levels within hundreds of tumors and used the signature to also define which genes from the malignant cells were correlated with T cell abundance in bulk tumors.

They uncovered both genes whose expression was repressed — such as ones involved in antigen presentation and processing, interferon signaling, and immune modulation — and induced — such as CDK4 and its targets. The researchers noted that the immune resistance program encompasses the hallmarks of immune evasion, suppression and exclusion. 

They also found that this gene expression program appears to intrinsic. It is found in untreated tumors — in particular, they noted it is present in a subset of about 24 percent of malignant cells in about 80 percent of untreated tumors. The program does become more common following immune checkpoint inhibitors therapy failure, the team added.

It can also predict how patients would respond to immune checkpoint inhibitor treatment, the researchers reported. In the TCGA cohort, expression of the program was linked to poor survival. Further, in a separate cohort, they found that its expression could distinguish immune checkpoint inhibitor responders from non-responders.

It also could predict progression-free survival, as well as complete response, better than the 47 other signatures tested.

The researchers suspected that CDK4/6 might be master regulators of this gene expression program and that targeting them might reverse resistance. They tested the CDK4/6 inhibitor abemaciclib in three melanoma cell lines and found it appeared to repress the program and lead to cell senescence. They also tested it in conjunction with immune checkpoint inhibitor treatment in a mouse model of immunotherapy-resistant melanoma. There, abemaciclib appeared to sensitize the mice to treatment.

This, the researchers said, suggests a means to overcome immunotherapy resistance and could be applicable to other cancer types. They are now starting a clinical trial to further explore this combination treatment. "Our work, along with that of colleagues studying the effects of CDK4/6 inhibitors in breast cancer and other diseases, provides a rationale for exploring combination therapy with immune checkpoint inhibitors," co­senior author Benjamin Izar, a melanoma oncologist at Dana­Farber Cancer Institute and postdoc at the Broad, said in a statement.

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