Extricating human tumor-unique immune alterations from non-malignant tissue inflammation

Abstract Immunotherapies to treat cancer have achieved remarkable successes, but major challenges persist. An inherent weakness of current treatment approaches is that therapeutically targeted pathways are not only found in tumors, but also in tissue microenvironments, particularly inflamed tissues. This confounding overlap complicates treatment as well as predictions of treatment outcome. In an effort to identify potential tumor-unique immunotherapeutic targets that are distinct from general tissue inflammation, we used complementary single-cell analysis approaches to interrogate immune cell alterations and interactions in human squamous cell carcinomas and site-matched non-malignant, inflamed tissues. We found that a distinct population of intratumoral regulatory T cells (Tregs) received T cell receptor (TCR) signals from antigen-presenting cells and this Treg population was uniquely identified by co-expression of ICOS and IL-1 receptor type 1 (IL-1R1). Intratumoral IL-1R+ Tregs appeared activated and a TCR signal was sufficient to convert IL-1R1- Tregs to IL-1R1+ Tregs ex vivo. Overall, our work identifies an intratumoral Treg population that recognizes antigen in the tumor microenvironment and two biomarkers that allow for specific depletion of these Tregs. Finally, our approach also provides a blueprint for extricating tumor-unique therapeutic targets distinct from general inflammatory patterns in other tumors.