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.

Genomic Landscape of Atypical Adenomatous Hyperplasia Reveals Divergent Modes to Lung Adenocarcinoma

“…For instance, monoclonal antibodies targeting genes such as CD27 and CTLA-4 are already being tested for treatment of various cancers including lung adenocarcinomas [43]. In this context and as alluded to previously [44,45], our findings suggest that targeting immune responses and signaling (e.g., immune checkpoint blockade) may be a viable strategy to prevent progression of preneoplasia such as AAH.…”

Association Between Inflammatory Diet Pattern and Risk of Colorectal Carcinoma Subtypes Classified by Immune Responses to Tumor

“…8, 9 During the processes of inflammation and tumorigenesis, a neoplastic lesion recruits various innate and adaptive immune cells. These immune cells communicate with each other by means of direct contact or cytokine and chemokine production to control and shape tumor growth.…”

Immunological and classical subtypes of oral premalignant lesions

“…41 Overall, the interaction between the immune system and neoplasia reflects a fundamental principle, applicable to all organ/cell types. 42 The recent success of the use of PD-1 immune checkpoint blockade in advanced HNSCC 43–45 confirms the clinical importance of immune modulation in this context. Overall, tumors orchestrate a complex signaling network to induce immune tolerance.…”