Overcoming Resistance to Immunotherapy in Cancer

A new study published by Nature pinpoints several genes necessary for effective cancer immunotherapy, which may address why some patients do not respond to the treatment or develop resistance.

Immunotherapy has grown in popularity recently, as it may provide patients with a less toxic approach to cancer treatment compared with chemotherapy or radiation.

“There is a great deal of interest in cancer immunotherapy, especially for patients who have metastatic cancer,” said lead researcher Nicholas Restifo, MD. “The response to immunotherapy can be fantastic, but understanding why some patients don’t respond will help us improve treatments for more patients.”

T cells are central to the mechanisms used by immunotherapies to kill tumors. The authors have previously found that infusions of T cells can induce regression in patients with cancer.

While T cells can recognize and eliminate cancer cells, some are resistant to the attacks. To determine the underlying causes of this resistance, the authors aimed to identify genes in cancer cells that leave them vulnerable to T cells.

In the study, the authors used the gene-editing tool CRISPR to knock out the expression of individual genes in a melanoma cancer cell line. The authors knocked out every known protein-encoding gene and tested the ability of the modified melanoma cells to respond to T cells.

The investigators discovered more than 100 genes that possibly play a role in the elimination of cancer cells by T cell attacks, according to the study.

The authors then looked for additional evidence that these genes increase vulnerability to T cell attacks. They examined data about cytolytic activity—a genetic profile that shows cancer cells responding to T cells—in more than 11,000 patient tumors from The Cancer Genome Atlas.

The researchers found that multiple genes were linked to tumor cytolytic activity in patient samples, according to the study.

The APLNR gene, which produces the apelin receptor protein, was found to be involved in T cell response. Further analysis indicated that the protein was not functional in some patients with immunotherapy-resistant cancers, according to the study.

“Many more genes than we originally expected play a vital role in dictating the success of cancer immunotherapies,” said first study author Shashank Patel, PhD.

The authors believe that this list of genes could be used to better study immunotherapy-resistant cancers. If validated in clinical trials, these findings could be harnessed to develop better immunotherapy, according to the study.

“If we can truly understand mechanisms of resistance to immunotherapy, we might be able to develop new therapeutics,” Dr 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."