Abstract
It was recently reported that acute influenza infection of the lung promoted distal melanoma growth in the dermis of mice. Melanoma-specific CD8+ T cells were shunted to the lung in the presence of the infection, where they expressed high levels of inflammation-induced cell-activation blocker PD-1, and became incapable of migrating back to the tumor site. At the same time, co-infection virus-specific CD8+ T cells remained functional while the infection was cleared. It was also unexpectedly found that PD-1 blockade immunotherapy reversed this effect. Here, we proceed to ground the experimental observations in a mechanistic immunobiochemical model that incorporates T cell pathways that control PD-1 expression. A core component of our model is a kinetic motif, which we call a PD-1 Double Incoherent Feed-Forward Loop (DIFFL), and which reflects known interactions between IRF4, Blimp-1, and Bcl-6. The different activity levels of the PD-1 DIFFL components, as a function of the cognate antigen levels and the given inflammation context, manifest themselves in phenotypically distinct outcomes. Collectively, the model allowed us to put forward a few working hypotheses as follows: (i) the melanoma-specific CD8+ T cells re-circulating with the blood flow enter the lung where they express high levels of inflammation-induced cell-activation blocker PD-1 in the presence of infection; (ii) when PD-1 receptors interact with abundant PD-L1, constitutively expressed in the lung, T cells loose motility; (iii) at the same time, virus-specific cells adapt to strong stimulation by their cognate antigen by lowering the transiently-elevated expression of PD-1, remaining functional and mobile in the inflamed lung, while the infection is cleared. The role that T cell receptor (TCR) activation and feedback loops play in the underlying processes are also highlighted and discussed. We hope that the results reported in our study could potentially contribute to the advancement of immunological approaches to cancer treatment and, as well, to a better understanding of a broader complexity of fundamental interactions between pathogens and tumors.
Highlights
It was recently reported that acute influenza A infection (A/H1N1/PR8) of the lung promoted distal B16-F10 skin melanoma growth in the dermis [1]
The selected mechanisms will be formalized in terms of a relevant genetic molecular circuit (PD-1 Double Incoherent Feed-Forward Loop (DIFFL)) that regulates PD-1 expression
Our proposed PD-1 DIFFL model is based upon molecular detail discovered previously, and is independent of the results obtained in Kohlhapp et al [1]
Summary
It was recently reported that acute influenza A infection (A/H1N1/PR8) of the lung promoted distal B16-F10 skin melanoma growth in the dermis [1]. It was unexpectedly found that blockade of PD-1 resulted in reversal of infection-mediated anti-tumor response disruption In this respect, it is very important to mention that the work by Kohlhapp et al [1] was primarily motivated by two still unmet challenges: (i) emerging epidemiological studies reporting an increased cancer prevalence and cancer-specific deaths in patients with infections [1], and (ii) despite the fact that tremendous amount of work on immune response in the context of pathogenic co-infection has been done, findings in this field still remain discordant and a matter of debate, as reviewed by Kohlhapp et al [1] and Zloza [2]. A literature review of the corresponding mechanistic detail, the model construction, and the model’s parameter justification can be found in Supplementary Material
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