Immunobiochemical reconstruction of influenza lung infection - Melanoma skin cancer interactions

Abstract

Our recent experimental results that combine a mouse model of influenza A virus (IAV) infection (A/H1N1/PR8) and a highly aggressive model of infection-unrelated cancer, B16-F10 skin melanoma, showed that acute influenza infection of the lung promotes distal melanoma growth in the dermis of the flank and leads to decreased host survival. Here, we proceed to ground the experimental observations in a mechanistic immunobiochemical model that incorporates the T cell receptor signaling pathway, various transcription factors, and a gene regulatory network (GRN).A core component of our model is a biochemical motif, which we call a Triple Incoherent FeedForward Loop (TIFFL), and which reflects known interactions between IRF4, Blimp-1, and Bcl-6.The different activity levels of the TIFFL components, as a function of the cognate antigen levels and the given inflammation context, manifest themselves in phenotypically distinct outcomes.Specifically, both the TIFFL reconstruction and quantitative estimates obtained from the model allowed us to formulate a hypothesis that it is the loss of the fundamental TIFFL-induced adaptation of the expression of PD-1 receptors on anti-melanoma CD8+ T cells that constitutes the essence of the previously unrecognized immunologic factor that promotes the experimentally observed distal tumor growth in the presence of acute non-ocogenic infection. We therefore hope that this work can further highlight the importance of adaptive mechanisms by which immune functions contribute to the balance between self and non-self immune tolerance, adaptive resistance, and the strength of TCR-induced activation, thus contributing to the understanding of a broader complexity of fundamental interactions between pathogens and tumors.2 All rights reserved. No reuse allowed without permission.(which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.

Delicate balances in cancer chemotherapy: Modeling immune recruitment and emergence of systemic drug resistance

“…A similar paradoxical effect is that of the effect of treatment on cancer growth: on the one hand, the drug directly attacks the tumor, but on the other hand, through "friendly fire" also attenuates immune activity, thus degrading the anti-tumor response. IFFLs constitute one of the core network motifs in systems biology [64], and are found in processes as varied as gene regulation, immune recognition, synthetic biology, and bacterial motion [65,66,67,68,69,70]. Fig.…”