UCSF scientists find a trove of new targets for cancer immunotherapy in cancer’s unique version of RNA splicing.

Immune therapy has transformed how cancer is treated, but many tumors continue to evade these treatments, thanks to their resemblance to healthy tissue.

Now, researchers at UC San Francisco have found that some cancers, like brain cancer (glioma), make unique, jumbled proteins that make them stand out. These newly recognized cancer-specific proteins, or antigens, could speed the development of potent immunotherapies that recognize and attack hard-to-treat tumors.

The study, which was supported through grants from the National Institutes of Health, appears in Nature on Feb. 19.

The newly discovered antigens were the product of mistakes in RNA splicing, which controls how RNA molecules – the blueprints for proteins – are pieced together from smaller parts. The study found that in cancers of the brain, prostate, liver and colon, among others, the tumors spliced together bits of RNA to create new forms that had never been seen before, and which were absent in healthy tissues.

Some of these new RNAs produced antigens that attached to the surface of tumor cells, creating an entry for immune therapy. The researchers then engineered immune T-cells to recognize these antigens and were able to destroy glioma in the lab.

Such antigens from alternative RNA splicing could vastly expand the number of targets available for immunotherapy – and the options available to patients in need of a cure.

“We think these first antigens could be actionable in the near future, leading to new therapies for glioma patients,” said Hideho Okada, MD, PhD, professor of neurosurgery at UCSF and co-corresponding author of the paper. “But they are the tip of the iceberg and we’re excited to look into many more from the data we generated.”

Fishing antigens from a sea of RNA

Precision medicine today relies on either drugs that disable the mutant proteins that cause cancer or on the immune cells that track down cancer-related antigens. But many tumors don’t have such mutant proteins or antigens. Even if they do, those targets might not cover all of a tumor.

“One of the reasons we think a lot of glioma therapies fail is that they only target one part of the tumor. The rest of the tumor escapes unscathed,” said Joe Costello, PhD, professor of neurosurgery at UCSF and co-corresponding author of the paper. “These new antigens lift us over that major hurdle of brain tumor heterogeneity.”

To hunt for new targets for cancer therapies, Darwin Kwok, PhD, focused on RNA splicing, which sometimes produces several versions of a protein based on a single gene.

“Many cancer therapies today are based on unique DNA mutations found in tumors, but we suspected that tumors might also have altered RNA splicing leading to new cancer-specific antigens,” said Kwok, who is a PhD graduate from the Okada and Costello labs, current UCSF medical student, and first author of the paper.

Kwok pored through RNA sequencing data from thousands of tumors held by The Cancer Genome Atlas, a program at the National Cancer Institute. He homed in on uniquely spliced RNA messages (mRNAs) that were consistently found in multiple biopsies per tumor and in multiple patients. The tumors came from prostate, liver, colon, stomach, kidney and lung cancers.

He also teamed up with the UCSF Brain Tumor Center to look for these mRNAs in glioma samples donated by 51 UCSF patients. The researchers obtained up to 10 biopsies per tumor, kept track of where in each tumor each biopsy had come from, and again looked for unusual mRNAs.

From this broad analysis, the team found nearly 1,000 cancer-specific mRNAs, common across tumors, cancer types and patients, that had never been documented. None were ever found in healthy tissue.