Characterizing immune crosstalk in the precancerous tissue

Abstract

Extensive work within the field of cancer immunology has successfully characterized the tumor immune microenvironment and its impact on patient responses to therapy. However, there has been substantially less work dedicated to understanding the early factors that facilitate the formation of the tumor immune microenvironment. In particular, understanding changes in early precancerous cells and the subsequent impact on the precancerous tissue may facilitate our understanding of how the tumor microenvironment forms. In this thesis, we demonstrate that precancerous cells alter their communication with the other cells in their environment well before the formation of a tumor. Leveraging an established model of cutaneous squamous cell carcinoma (cSCC), we find that keratinocytes with carcinogenic mutations change their signaling to both local immune cells and the local neuron population. Mechanistically, precancerous keratinocytes upregulate the expression of cytokines Ccl20 and Thymic Stromal Lymphopoietin (Tslp). These cytokines are known to control the Innate Lymphoid Cell (ILC) population in other skin pathologies. Further, their upregulation by the precancerous keratinocytes coincides with an expansion in the skin ILC population in the precancerous skin. In addition to these cytokines, we also note that the precancerous keratinocytes substantially upregulate Peptide YY (Pyy). We find Pyy receptor expression exclusively within a subset of dermal neurons. We also find that the neuron population within the precancerous skin changes and upregulates expression of genes associated with neuronal regeneration, suggesting the neuron population is becoming poised to engage. Collectively, this work demonstrates that well before the formation of a palpable tumor, precancerous cells alter their communication with their microenvironment. This altered communication demonstrates that the formation of the tumor microenvironment likely starts well before a tumor even exists.