Modeling the Th17 and Tregs Paradigm: Implications for Cancer Immunotherapy.

CD4 + T cell differentiation is governed by gene regulatory and metabolic networks, with both networks being highly interconnected and able to adapt to external stimuli. Th17 and Tregs differentiation networks play a critical role in cancer, and their balance is affected by the tumor microenvironment (TME). Factors from the TME mediate recruitment and expansion of Th17 cells, but these cells can act with pro or anti-tumor immunity. Tregs cells are also involved in tumor development and progression by inhibiting antitumor immunity and promoting immunoevasion. Due to the complexity of the underlying molecular pathways, the modeling of biological systems has emerged as a promising solution for better understanding both CD4 + T cell differentiation and cancer cell behavior. In this review, we present a context-dependent vision of CD4 + T cell transcriptomic and metabolic network adaptability. We then discuss CD4 + T cell knowledge-based models to extract the regulatory elements of Th17 and Tregs differentiation in multiple CD4 + T cell levels. We highlight the importance of complementing these models with data from omics technologies such as transcriptomics and metabolomics, in order to better delineate existing Th17 and Tregs bifurcation mechanisms. We were able to recompilate promising regulatory components and mechanisms of Th17 and Tregs differentiation under normal conditions, which we then connected with biological evidence in the context of the TME to better understand CD4 + T cell behavior in cancer. From the integration of mechanistic models with omics data, the transcriptomic and metabolomic reprograming of Th17 and Tregs cells can be predicted in new models with potential clinical applications, with special relevance to cancer immunotherapy.