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NCI Researchers Uncover Genes Needed for Effective Cancer Immunotherapy

NEW YORK (GenomeWeb) – A US National Cancer Institute-led team has come up with a list of genes that appear to be essential for T cell-based immunotherapies to be effective in treating cancer.

While immunotherapies have been successful in treating a number of cancer patients, others appear resistant to their effects. Using a CRISPR-based screen they developed, NCI's Nicholas Restifo and his colleagues searched for genes that, when altered, make cells refractory to immunotherapies. As they reported in Nature today, the researchers uncovered a host of genes that are needed for immunotherapies to work. They particularly focused on APLNR to find that it interacts with the JAK-STAT signaling pathway to influence T-cell recognition.

"We cast a wide, deep net and conducted an unbiased survey of all of the 19,000 genes in the cancer's genome — not just the genes that are known to be involved in creating immunotherapy-resistant tumors," Restifo said in a statement. "The big surprise was that we found many new genes that we never suspected could potentially be involved in preventing the immune system from killing cancer cells."

He and his colleagues developed a 'two-cell type' CRISPR assay system (2CT CRISPR) to examine how mutations in one cell affect its interactions with another. In their study, they used the CRISPR gene-editing tool to knock out protein-coding genes in melanoma cells to see how their loss influenced the cells' interactions with T cells. Current immunotherapies rely on engineering T cells to better recognize and attack cancer cells.

In their study, the researchers systematically tested the effects of some 19,000 genes on T-cell response. From this, the researchers found more than 100 genes that may be involved in the development of T cell-resistant cancer cells, including HLA-A, B2M, and SOX10.

The researchers correlated the genes they uncovered in their 2CT CRISPR screen with a Cancer Genome Atlas dataset of more than 11,000 tumors, representing 35 cancer types. The genes identified through their screen were enriched for antigen presentation, interferon-gamma signaling, and cytolytic activity.

The researchers especially noted 19 genes that were associated with cytolytic activity across the three dozen cancer types. About half these genes, they found, were inducible by IFN-gamma. Loss of expression of these 19 genes led to a decline in tumor antigen presentation, T cell co-stimulation, or cytokine production and signaling.

Restifo and his colleagues focused on one such gene, APLNR, which encodes a G-protein coupled receptor called apelin that's mutated in a number of cancers. They found that it interacts with the JAK-STAT signaling pathway, which is involved in immune response. In particular, they reported that APLNR interacts with JAK1 to modulate IFN-gamma response.

IFN-gamma drives the phosphorylation of JAK1 to stimulate the JAK-STAT signaling pathway, which leads to increased antigen processing and presentation by tumors. That, in turn, improves the ability of T cells to recognize and attack those cells.

When the researchers introduced APLNR mutations they uncovered in immunotherapy-resistant patient tumors into a melanoma cell line, they found that T cells were then less able to attack the melanoma cells. In a mouse cancer model, they further found that APLNR loss led to poor prognosis and blocked immunotherapy treatment.

"If we can truly understand mechanisms of resistance to immunotherapy, we might be able to develop new therapeutics," Restifo said. "In fact, in the future, this knowledge could speed the development of a new category of drugs that can circumvent these escape mechanisms of tumor cells and help patients experience complete responses."