Cytokine/chemokine profiles in squamous cell carcinoma correlate with precancerous and cancerous disease stage

Zewen K Tuong,Raymond J Steptoe,Richard Lewandowski,Ian H Frazer,H Peter Soyer,Jennifer A Bridge,James W Wells,Miko Yamada,Graham R Leggatt,Duncan Lambie,Jazmina L G Cruz,Andrew Lewandowski,Fiona Simpson

doi:10.1038/s41598-019-54435-0

Abstract

Actinic Keratosis (AK), Intraepidermal Carcinoma (IEC), and Squamous Cell Carcinoma (SCC) are generally considered to be advancing stages of the same disease spectrum. However, while AK often regress spontaneously, and IEC often regress in response to immune-activating treatments, SCC typically do not regress. Therefore, it is vital to define whether fundamental immunological changes occur during progression to SCC. Here we show that proinflammatory cytokine expression, chemokine expression, and immune cell infiltration density change during progression to SCC. Our findings suggest a switch from predominantly proinflammatory cytokine production to chemokine production is a key feature of progression from precancer to cancer. Together, these observations propose a model that can underpin current research and open new avenues of exploration into the clinical significance of these profiles with respect to immunotherapeutic or other treatment outcomes.

Highlights

Actinic Keratosis (AK), Intraepidermal Carcinoma (IEC), and Squamous Cell Carcinoma (SCC) are generally considered to be advancing stages of the same disease spectrum
We recently examined the abundance of T cells in AK, IEC, and SCC lesions taken from immunocompetent patients and discovered that there is a decreased abundance of CD8 T cells in SCC compared with IEC11
The analysis suggests that (i) up-regulation of proinflammatory cytokines is a feature in AK that separates it from normal skin, (ii) the altered chemokine profile of IEC and SCC is more pronounced than that of AK, and (iii) SCC disease stages are separable into distinct cohorts based on immune cell infiltration, proinflammatory cytokine expression, and chemokine expression, with a corresponding difference in lesion thickness

Summary

Introduction

Actinic Keratosis (AK), Intraepidermal Carcinoma (IEC), and Squamous Cell Carcinoma (SCC) are generally considered to be advancing stages of the same disease spectrum. The differences in the immune environment associated with each disease stage remain poorly defined It has been appreciated for more than 40 years that SCC are highly immunogenic tumours that are quickly rejected when adoptively transferred from UV-treated mice into immune competent mice, but not rejected when adoptively transferred into thymectomized mice[6]. By characterizing the cytokine profiles of AK, IEC, and SCC disease stages we sought to determine whether an alteration in the expression levels of key proinflammatory cytokines, or a change in chemokine secretion bias, may provide an indication for the reduced numbers of CD8 T cells that infiltrate into SCC

Methods

Results

Conclusion