Emerging Prognostic and Predictive Factors in Pancreatic Cancer

Abstract

Pancreatic cancer is a lethal disease with increasing incidence and high recurrence rates and is currently resistant to conventional therapies. Moreover, it displays extensive morphologic and molecular intratumoral and intertumoral heterogeneity and a mostly low mutational burden, failing to induce significant antitumor immunity. Thus, immunotherapy has shown limited effect in pancreatic cancer, except in rare tumors with microsatellite instability, constituting <1% of the cases. Currently, new methods, including single-cell and single-nucleus RNA sequencing, have refined and expanded the 2-group molecular classification based on bulk RNA sequencing (classical and basal-like subtypes), identifying hybrid forms and providing us with a comprehensive map of the tumor cell subsets that drive gene expression during tumor evolution, simultaneously giving us insight into therapy resistance and metastasis. Additionally, deeper profiling of the tumor microenvironment of pancreatic cancer by using spatial analyses and multiplex imaging techniques has improved our understanding of the heterogeneous distribution of both adaptive and innate immune components with their protumor and antitumor properties. By integrating host immune response patterns, as defined by spatial transcriptomic and proteomic analysis and multiplex immunofluorescence, with molecular and morphologic features of the tumors, we can increasingly understand the genetic, immunologic, and morphologic background of pancreatic cancer and recognize the potential predictors for different treatment modalities.

Keywords: PD-L1; genetic alterations; microsatellite instability; molecular subtypes; pancreatic cancer; tumor microenvironment; tumor mutational burden.