April 29, 2014 – Developing immunotherapies for cancer is challenging because of significant variability among tumors and diversity in human immune types. In a study published online today in Genome Research, researchers examined the largest collection of tumor samples to date to predict patient-specific tumor mutations that may activate the patient's immune system, paving the way for more successful, personalized cancer immunotherapy.
Tumor cells accrue mutations in their DNA, and as these mutations accumulate, the cell looks less and less like part of the body and more like a foreign invader to the immune system. Cancer patients with stronger anti-tumor immune responses, mediated by T cells, are more likely to live longer. Much research has focused on strategies to harness the immune system to fight cancer; however, it has been difficult to determine the tumor mutations that activate a patient's T cells because the mutations occur sporadically, and successful activation depends on the patient's immune type (specifically, their HLA type), which varies considerably from person to person.
In this new study, the authors used a collection of over 500 tumor samples to computationally predict, using both the mutation profile and the individual's immune type, which tumor mutations are likely to be "immunogenic," causing an immune response in the patient. They found that patients with one or more immunogenic mutations had higher expression of a known T cell marker, indicative of an anti-tumor T cell response. Furthermore, these patients had higher overall survival rates than patients without immunogenic mutations, suggesting the mutations are eliciting a protective immune response.
This study highlights the "personalized nature of the tumor-immune interaction" said the lead author of the study, Robert Holt. "Cancer immunotherapy is most likely to be successful if it is personalized, that is, targeted to each individual patient's immune type and mutation profile." With the decreasing cost of DNA sequencing, "it is now feasible to map these mutational profiles and design individual vaccines in relatively short order," Holt said.
Furthermore, the study demonstrates that tumors harboring large numbers of mutations are more likely to benefit from cancer immunotherapy, because they are more likely to have mutations that make the tumor susceptible to the immune system.
Holt added, "these results also support an entirely new approach to immunotherapy: creating personalized cancer vaccines that use tumor-specific immunogenic mutations to enhance anti-tumor immunity." The team is now looking to apply this strategy in combination with conventional cancer therapies.
The data in this study was generated by The Cancer Genome Atlas (TCGA), a comprehensive resource of genomic information from a large number of patient samples, funded by the U.S. National Institutes of Health.
Scientists from BC Cancer Agency, University of British Columbia, University of Victoria, and Simon Fraser University contributed to this study.
This work was supported by funding from the BC Cancer Foundation, Canadian Institutes of Health Research, and the U.S. Department of Defense.
Media contacts: The authors are available for more information by contacting: Jenn Currie, Communications Officer, BC Cancer Agency (jenn.currie@bccancer.bc.ca, +1-604-675-8106)
Interested reporters may obtain copies of the manuscript via email from Peggy Calicchia, Administrative Assistant, Genome Research (calicchi@cshl.edu, +1-516-422-4012).
About the article: The manuscript will be published online ahead of print on 29 April 2014. Its full citation is as follows: Brown SD, Warren RL, Gibb EA, Martin SD, Spinelli JJ, Nelson BH, Holt RA. 2014. Neo-antigens predicted by tumor genome meta-analysis correlate with increased patient survival. Genome Res doi: 10.1101/gr.165985.113
About Genome Research: Launched in 1995, Genome Research is an international, continuously published, peer-reviewed journal that focuses on research that provides novel insights into the genome biology of all organisms, including advances in genomic medicine. Among the topics considered by the journal are genome structure and function, comparative genomics, molecular evolution, genome-scale quantitative and population genetics, proteomics, epigenomics, and systems biology. The journal also features exciting gene discoveries and reports of cutting-edge computational biology and high-throughput methodologies.
About Cold Spring Harbor Laboratory Press: Cold Spring Harbor Laboratory is a private, nonprofit institution in New York that conducts research in cancer and other life sciences and has a variety of educational programs. Its Press, originating in 1933, is the largest of the Laboratory's five education divisions and is a publisher of books, journals, and electronic media for scientists, students, and the general public.
Genome Research issues press releases to highlight significant research studies that are published in the journal.
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