Abstract: Clonal evolution of a tumoral ecosystem is a function of a wide spectrum of selection pressures, principally encompassed by resource constraints and immune response. The clinical manifestation is intra-tumoral heterogeneity (ITH), a well-known survival and treatment efficacy correlate in many cancers. In a recent study (currently under review) we used multi-regional omics data to quantify how ITH can be modulated by an infiltrating adaptive immune response and viral co-factors, which in turn often dictate the efficacy of treatment. One key clinical question made all the more urgent by the ongoing pan-cancer immunotherapy revolution is to quantify ITH relative to the sampling bias of a single diagnostic biopsy. In this talk I will briefly describe the immune landscape of ITH and trace out two approaches we developed to estimate sampling bias and how they lead to some surprising bounds on clonal evolution and its associated phase space volume.