Tumor-immune metaphenotypes orchestrate an evolutionary bottleneck that promotes metabolic transformation

Jeffrey West^{1, 2} Frederika Rentzeperis³ Casey Adam⁴ Rafael Bravo² Kimberly A. Luddy² Mark Robertson-Tessi² Alexander R. Anderson^2*

• ¹Moffitt Cancer Center, United States
• ²Department of Integrated Mathematical Oncology, Moffitt Cancer Center, United States
• ³Icahn School of Medicine at Mount Sinai, United States
• ⁴Department of Engineering Science, Mathematical, Physical and Life Sciences Division, University of Oxford, United Kingdom

Metabolism plays a complex role in the evolution of cancerous tumors, including inducing a multifaceted effect on the immune system to aid immune escape. Immune escape is, by definition, a collective phenomenon by requiring the presence of two cell types interacting in close proximity: tumor and immune. The microenvironmental context of these interactions is influenced by the dynamic process of blood vessel growth and remodelling, creating heterogeneous patches of well-vascularized tumor or acidic niches. We present a multiscale mathematical model that captures the phenotypic, vascular, microenvironmental, and spatial heterogeneity which shapes acid-mediated invasion and immune escape over a biologically-realistic time scale. We model immune escape mechanisms such as i) acid inactivation of immune cells, ii) competition for glucose, and iii) inhibitory immune checkpoint receptor expression (PD-L1) under anti-PD-L1 and sodium bicarbonate buffer therapies. To aid in understanding immune escape as a collective cellular phenomenon, we define immune escape in the context of six collective phenotypes (termed "meta-phenotypes"): Self-Acidify, Mooch Acid, PD-L1 Attack, Mooch PD-L1, Proliferate Fast, and Starve Glucose. Fomenting a stronger immune response leads to initial benefits but this advantage is offset by increased cell turnover that accelerates the emergence of aggressive phenotypes by inducing an evolutionary bottleneck. This model helps to untangle the key constraints on evolutionary costs and benefits of three key phenotypic axes on tumor invasion and treatment: acid-resistance, glycolysis, and PD-L1 expression. The benefits of concomitant anti-PD-L1 and buffer treatments is a promising treatment strategy to limit the adverse effects of immune escape.