A new study identifies essential genes for cancer immunotherapy

A new study identifies genes that are necessary in cancer cells for immunotherapy to work, addressing the problem of why some tumors don’t respond to immunotherapy or respond initially but then stop as tumor cells develop resistance to immunotherapy.

NCI researchers have identified genes that are essential for cancer cells to be killed by T cells. Image credit: Jonathan Bailey, NHGRI

Cancer immunotherapy relies on T cells, a type of cell in the immune system, to destroy tumors. The team from the National Cancer Institute (NCI) have previously shown that the infusion of large numbers of T cells can trigger complete regression of cancer in patients. They and others have also shown that T cells can directly recognize and kill tumor cells.

However, some tumor cells are resistant to the destruction unleashed by T cells. To investigate the basis for this resistance, the researchers sought to identify the genes in cancer cells that are necessary for them to be killed by T cells.

Working with a melanoma tumor cell line, the researchers used a gene editing technology called CRISPR that “knocks out,” or stops the expression, of individual genes in cancer cells. By knocking out every known protein-encoding gene in the human genome and then testing the ability of the gene-modified melanoma cells to respond to T cells, they found more than 100 genes that may play a role in facilitating tumor destruction by T cells.

Once the team identified these “candidate” genes, they sought additional evidence that these genes play a role in susceptibility to T cell-mediated killing.

To this end, they examined data on “cytolytic activity,” or a genetic profile that shows cancer cells are responding to T cells, in more than 11,000 patient tumors from The Cancer Genome Atlas. They found that a number of the genes identified in the CRISPR screen as being necessary for tumor cells to respond to T cells were indeed associated with tumor cytolytic activity in patient samples.

One such gene is called APLNR. The product of this gene is a protein called the apelin receptor. Although it had been suspected to contribute to the development of some cancers, this was the first indication of a role in the response to T cells.

Further investigation of tumors from patients resistant to immunotherapies showed that the apelin receptor protein was nonfunctional in some of them, indicating that the loss of this protein may limit the response to immunotherapy treatment.

Many more genes play a vital role in dictating the success of cancer immunotherapies. (National Institutes of Health)

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