An evolutionary perspective on anti-tumor immunity

David J. Klinke

The challenges associated with demonstrating a durable response using molecular-targeted therapies in cancer has sparked a renewed interest in viewing cancer from an evolutionary perspective. Evolutionary processes have three common traits: heterogeneity, dynamics, and a selective fitness landscape. Mutagens randomly alter the genome of host cells creating a population of cells that contain different somatic mutations. This genomic rearrangement perturbs cellular homeostasis through changing how cells interact with their tissue microenvironment. To counterbalance the ability of mutated cells to outcompete for limited resources, control structures are encoded within the cell and within the organ system, such as innate and adaptive immunity, to restore cellular homeostasis. These control structures shape the selective fitness landscape and determine whether a cell that harbors particular somatic mutations is retained or eliminated from a cell population. While next-generation sequencing has revealed the complexity and heterogeneity of oncogenic transformation, understanding the dynamics of oncogenesis and how cancer cells alter the selective fitness landscape remain unclear. In this technology review, we will summarize how recent advances in technology have impacted our understanding of these three attributes of cancer as an evolutionary process. In particular, we will focus on how advances in genome sequencing have enabled quantifying cellular heterogeneity, advances in computational power have enabled explicit testing of postulated intra- and intercellular control structures against the available data using simulation, and advances in proteomics have enabled identifying novel mechanisms of cellular cross-talk that cancer cells use to alter the fitness landscape.