Immune predation promotes aggressive metabolic phenotypes in a context-dependent manner

Metabolism plays a complex but key role in the evolution of cancerous tumors. Localized hypoxia due to vascular dysfunction within the tumor microenvironment facilitates the metabolic response of the tissue (the Pasteur effect), causing acidification that leads to the evolutionary selection of acid-resistant tumor cell phenotypes. The subsequent emergence of a glycolytic phenotype in poor nutrient conditions leads to subsequent aggressive invasion. This evolutionary trajectory from normal to acid-resistant to glycolytic, is highly nonlinear and is modulated by vascular dynamics as well as the immune response. We present a multiscale hybrid-discrete-continuum cellular automata model that captures the phenotypic, vascular, microenvironmental, and spatial heterogeneity that shape acid-mediated invasion over biologically-realistic temporal scales. Specifically, we explore two major components in the interplay between tumor metabolism and immune function. First, T cells are subject to inactivation in acidic microenvironments. Second, competition for glucose inactivates the immune response through glucose starvation. These two processes are viewed as immune escape mechanisms that tumors may differentially employ in response to immune predation. A third mechanism considered is the expression of inhibitory immune checkpoint receptor (PD-L1). Model predictions indicate that fomenting a stronger immune response in a tumor leads to initial benefits with respect to additional cytotoxicity; however, this advantage is offset by the increased turnover of cells that leads to accelerated evolution and emergence of aggressive phenotypes. This creates a bimodal therapy landscape: either the immune system should be maximized for complete cure, or kept in check to avoid rapid evolution of invasive cells. The second option is akin to a natural adaptive therapy. These constraints are context-dependent and critically depend on the stability of intratumoral vascular dynamics and microenvironmental acidification.