Comprehensive Mapping of Tumor Immunity

Some cancer immunotherapy treatments work by targeting peptides that are presented on the surface of cancer cells by human leukocyte antigens (HLAs). However, immunotherapy treatment research tends to focus on only a small subset of HLAs, making many cancer patients unable to benefit from existing HLA-based immunotherapies. In a study published yesterday in eLife, scientists from the University Health Network, Toronto, Canada, have developed a new way to map these tumor-marking cell surface peptides.

“Most studies have focused on HLA proteins that are commonly found in the general population,” explains co–first author Kenji Murata. “We have developed a new technique that allows the sampling of underrepresented HLA proteins to find peptides or antigens that can induce an antitumor immune response. We can then stimulate the patient’s own immune cells with those peptides and give them back to the patient to help treat their cancer.”

The team began by isolating T cells from eight patients with melanoma. This patient group spanned 25 different types of HLAs, allowing the team to analyze T cell interactions with more than 800 different antigen peptides. All eight patient samples were positive for at least one of the peptide–HLA combinations. Additionally, this method allowed the team to discover new peptides recognized by the T cells.

Next, the team explored whether the T cells that reacted to the peptides could cause an immune response by measuring the production of an immune-activating molecule called interferon. All except two of the antigens stimulated the T cells to produce interferon and to increase in number. These effects were made more robust by adding to the T cells another type of cell—an artificially engineered antigen-presenting cell (APC) bearing the same antigen, which is a common strategy to stimulate T cells.

In the next stage, the team used the artificial APCs to find the exact immunogenic signal that stimulated the T cells from melanoma patients. They found novel peptide fragments related to two different antigens—MART1 and NY-ESO1—and looked at whether they could engineer T cells to target these novel antigens by cloning the T cell receptor (TCR) genes of cells that react against them.

“When we added these cloned TCR genes back into newly isolated T cells, we found that the cells were able to recognize and react to the tumor cells,” says co–first author Munehide Nakatsugawa.