Tumor Cells Molecules May Make Immunotherapy More Effective

Researchers have developed a new way to map the molecules on tumor cells that flag their presence to the immune system. Their findings could make commonly used immunotherapy treatments effective for a larger population of patients with cancer, according to a study published in eLife.

Certain cancer immunotherapy treatments work by targeting short pieces of proteins, known as peptides, which are displayed on the surface of cancer cells. Peptides are presented on the cell surface by human leukocyte antigens (HLAs), which have many different types. However, immunotherapy research tends to focus on a small subset of HLAs only. As not all patients with cancer produce these HLAs, they are unable to benefit from existing HLA-based immunotherapies.

"Most studies have focused on HLA proteins that are commonly found in the general population. We have developed a new technique that allows the sampling of underrepresented HLA proteins to find peptides or antigens that can induce an anti-tumor 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,” said Kenji Murata, co-first author, in a press release.

The researchers isolated T cells from 8 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. The 8 patient samples were positive for at least 1 of the peptide-HLA combinations. The methods developed here also 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 interferons. All except 2 of the antigens stimulated the T cells to produce interferons, as well as to stimulate the cells to increase in number. These effects were made more robust by adding to the T cells an artificially engineered antigen-presenting cell (APC) bearing the same antigen, which is a common strategy to stimulate T cells, according to the study.

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 2 different antigens, called MART1 and NY-ESO1, which are known to contain immunological hotspots, according to the study.

The researchers examined whether they could engineer T cells to target these novel antigens by taking cells that react against the novel antigens and cloning their T cell receptor (TCR) genes. TCRs are cell-surface proteins that allow T cells to react to antigens. When they added these cloned TCR genes back into newly isolated T cells, they found that the cells were able to recognize and react to the tumor cells.

"By querying human melanoma-derived T cells and using novel HLA proteins bearing common tumor antigens, we have been able to discover both new and existing immunologically active antigens in tumors. Our strategy allows for a more complete examination of the immune response and development of novel cancer vaccines and immunotherapies for a broader group of patients not limited by HLA prevalence or tumor mutation burden,” said senior author Naoto Hirano, in a press release.

References

• Comprehensive tumor immunity map opens up immunotherapy to more patients. EurekAlert website. Published April 21, 2020. https://www.eurekalert.org/pub_releases/2020-04/e-cti042120.php. Accessed April 30, 2020.