Macrophage-mediated immunoediting drives ductal carcinoma evolution: Space is the game changer

Abstract

Under normal conditions, the immune system is capable of rapidly detecting and eliminating potentially dangerous entities, including tumor cells. Due to intense selection pressure imposed by the immune response, tumor cells often evolve strategies to avoid elimination in a process known as immunoediting. It is less known how the evolutionary response to immune predation is altered by context. We explore the evolution of immune escape strategies in ductal cancers, a natural case in which to study evolution in different contexts: inside and outside of ducts. We highlight the role of macrophages as a source of "public goods," releasing diffusible factors (reactive oxygen species and growth factors). Immunohistochemistry reveals differences between macrophage densities of invasive ductal carcinomas and non-invasive ductal carcinomas in situ. For the first time, immunohistochemistry (IHC) imaging data comparing DCIS to IDC were used to initialize mechanistic agent-based models of evolutionary dynamics. By using IHC to map the initial conditions of a growing tumor, we show that spatial competition and structure influence transient dynamics during invasion. These dynamics are context-dependent, a conclusion that may be missed from interpreting imaging or non-spatial modeling alone. Before invasion, the presence of macrophages correlate with shorter ductal breach times. After invasion, tumors may employ a "pioneer-engineer" strategy where pioneering immunoresistant cells on the tumor's edge stimulate the release of M1-macrophage-derived reactive oxygen species, degrading surrounding stroma. Behind the invasive edge, the engineering immunosuppressive cells promote the release of M2-macrophage-derived growth factors, providing a long-term immune escape strategy. Together, mathematical modeling and image analysis highlight the crucial role tumor-associated macrophages play in immune escape and invasion, both inside and outside of ducts. 2/1513/15 14/15

Cancer systems immunology

“…PhysiCell analyses have revealed how gradients of immunogenicity can ‘trap’ immune cells at the tumor center and allow tumor cells at the outside to escape immune attack and reestablish a tumor ( Ozik et al, 2018 ). Another recent study combined EGT with ABM to model tumor invasion and show how subpopulations within tumors can co-opt distinct macrophage populations to both degrade stroma and suppress immune responses ( Gatenbee, 2019 ).…”

dN/dSdynamics quantify tumour immunogenicity and predict response to immunotherapy

“…We extended our previous modelling work to incorporate the acquisition of nonsynonymous and synonymous mutations in driver (positively selected) and passenger (neutral) loci 24,46,47 , as well as in regions exposed to the immune system and regions that confer immune-evasion properties (Fig 1). The interaction of different mutations and the observed evolutionary dynamics can be simplified into four phases: 1) A pre-neoplastic phase where cells do not have cancer driver mutations but may acquire passenger, immunogenic or escape mutations ( Fig 1A), 2) a neoplastic phase that begins when a driver mutation avoids stochastic drift and initiate a clonal expansion (Fig 1B), 3) an elimination phase where cells acquiring somatic mutations recognized by the immune system are eliminated ( Fig 1C), and 4) a phase where expanding clones lead to a clinically-detectable tumor through either depletion of immunogenic mutations (immune adapted) or through a mutation in the genome that triggers an immune escape mechanism (immune escaped) ( Fig 1D).…”

IsoMaTrix: a framework to visualize the isoclines of matrix games and quantify uncertainty in structured populations

“…While replicator dynamics has proven quite useful, the dynamics of spatially structured populations can vary dramatically 27,28 . In some cases, it is possible to create transforms of the replicator dynamics due to the specific spatial structures.…”