Cancer Cells Hide Immune Targets; Revealing Them Could Enable Treatment

A study has found that cancer immunotherapies may fail not because immune cells are weak, but because tumors hide their targets. The researchers proposed that changing tumors to reveal targets on their surface could help immune cells recognize cancer.

According to a report by Azure Life Science on the 18th (local time), researchers at Dana-Farber Cancer Institute in the United States uncovered how cancers with mutations in the tumor suppressor protein p53 hide those mutations from T cells. The study was published in the international journal Immunity.

T cells do not read a tumor’s DNA directly. Instead, they inspect peptides, or protein fragments, displayed by HLA molecules on the cell surface. If cancer-specific fragments do not appear on the surface or disappear too quickly, even powerful T cells cannot find a target to attack.

Mutations in TP53, the gene that produces p53, occur in about half of all cancers. Because they arise early and are “trunk” mutations shared by most cells in a tumor, they have attracted interest as targets for immunotherapy. But when the researchers used ultrasensitive mass spectrometry to measure peptides actually displayed on the surface, they found that p53 was exposed far less than expected.

Of 175 candidate wild-type p53 peptides, only 5 were definitively detected. Many common oncogenic p53 “hot spot” mutations were not processed properly and therefore failed to produce surface targets.

The researchers also identified additional escape routes. Some patient tumors lacked the HLA molecules needed to display potent p53 targets. In the case of the p53 I195F mutation, the ERAP1 enzyme was overactive and degraded highly immunogenic p53 fragments before they could be displayed on the surface. In experiments, removing or inhibiting ERAP1 enabled p53-specific T cells to recognize cancer cells again.

A different vulnerability emerged with the common p53 R175H mutation. The researchers identified a highly sensitive T-cell receptor that responded to even tiny amounts of the target, but the mutant p53 fragment bound too weakly to HLA molecules, making the complex unstable and short-lived. The receptor was capable, but the target itself was poor.

Ellis Reinherz, a professor at Dana-Farber Cancer Institute, said, “What the immune system cannot see, immunotherapy cannot attack.”

The researchers named the approach “immunopeptidome switching.” Rather than relying only on the peptides a tumor naturally displays, the idea is to use drugs to alter the antigen landscape so cancer cells reveal new peptide targets. Candidates include ERAP1 inhibitors, small molecules that bind HLA molecules and change which peptides can fit, and drugs that alter RNA splicing.

The strategy could help turn immunologically quiet “cold” tumors into “hot” tumors that attract immune cells. The researchers said it may have potential applications in pancreatic, prostate and ovarian cancers, brain tumors, and immunologically cold breast cancers.

The researchers said the findings also have implications for neoantigen drug development. Mutations predicted by tumor sequencing should not automatically be considered useful immune targets; peptides must be processed and presented, remain stable on the surface, and be recognizable by T-cell receptors.

“The traditional question has been how to make the immune system attack more forcefully,” Reinherz said. “Our results raise a complementary question: How can we make tumors reveal more?”

However, the study did not show that drugs actually converted cold tumors into hot tumors in patients. It identified mechanisms by which tumors suppress immune targets and experimentally confirmed that ERAP1-dependent peptide degradation can be reversed.

Researchers from Dana-Farber Cancer Institute and Harvard Medical School, as well as Vanderbilt University, Argonne National Laboratory and Boston Children’s Hospital, participated in the study.