Leveraging premalignant biology for immune-based cancer prevention

Abstract

Prevention is an essential component of cancer eradication. Next-generation sequencing of cancer genomes and epigenomes has defined large numbers of driver mutations and molecular subgroups, leading to therapeutic advances. By comparison, there is a relative paucity of such knowledge in premalignant neoplasia, which inherently limits the potential to develop precision prevention strategies. Studies on the interplay between germ-line and somatic events have elucidated genetic processes underlying premalignant progression and preventive targets. Emerging data hint at the immune system's ability to intercept premalignancy and prevent cancer. Genetically engineered mouse models have identified mechanisms by which genetic drivers and other somatic alterations recruit inflammatory cells and induce changes in normal cells to create and interact with the premalignant tumor microenvironment to promote oncogenesis and immune evasion. These studies are currently limited to only a few lesion types and patients. In this Perspective, we advocate a large-scale collaborative effort to systematically map the biology of premalignancy and the surrounding cellular response. By bringing together scientists from diverse disciplines (e.g., biochemistry, omics, and computational biology; microbiology, immunology, and medical genetics; engineering, imaging, and synthetic chemistry; and implementation science), we can drive a concerted effort focused on cancer vaccines to reprogram the immune response to prevent, detect, and reject premalignancy. Lynch syndrome, clonal hematopoiesis, and cervical intraepithelial neoplasia which also serve as models for inherited syndromes, blood, and viral premalignancies, are ideal scenarios in which to launch this initiative.

Keywords: biology; cancer prevention; immune oncology; premalignancy; vaccines.

Fig. 1.

The immunogenic repertoire of premalignancy. The horizontal lines at the bottom represent the layers of factors that can stimulate immunity, among them germ-line and somatic alterations and their complex dynamic interplay with the inflammatory TME (Upper Right). The upper half of the figure depicts the progressively immunosuppressive TME from left to right. The epithelial cells (middle row) illustrate two pathways of genomic instability on the left (irregular cell borders)—MSI and chromosomal instability—which can be inherited or acquired (see Colorectal Adenoma-Carcinoma Model). Inherited and acquired MSI-H lesions are highly immunogenic. The somatic cell alterations in the middle include complex posttranslational modifications (e.g., glycosylation), onco-fetal, and splice variants, important parts of the immunogenic repertoire, but their order in terms of cancer risk or immunogenicity is unclear. The cells on the far right middle row are virally infected cells, which have similar TME issues as the nonviral premalignancies. Vaccine-primed T-cells (Upper Left), capable of generating type I Th and CD8⁺ cells, could overcome early TME changes to eradicate cells in the transformation process.