Neoantigen Fitness Model Predicts Lower Immune Recognition of Cutaneous Squamous Cell Carcinomas Than Actinic Keratoses.

Elizabeth S Borden,Paul Kang,Heini M Natri,Melissa A Wilson,Tanya N Phung,Karen Taraszka Hastings,Kenneth H Buetow

doi:10.3389/fimmu.2019.02799

Abstract

A low percentage of actinic keratoses progress to develop into cutaneous squamous cell carcinoma. The immune mechanisms that successfully control or eliminate the majority of actinic keratoses and the mechanisms of immune escape by invasive squamous cell carcinoma are not well-understood. Here, we took a systematic approach to evaluate the neoantigens present in actinic keratosis and cutaneous squamous cell carcinoma specimens. We compared the number of mutations, the number of neoantigens predicted to bind MHC class I, and the number of neoantigens that are predicted to bind MHC class I and be recognized by a T cell receptor in actinic keratoses and cutaneous squamous cell carcinomas. We also considered the relative binding strengths to both MHC class I and the T cell receptor in a fitness cost model that allows for a comparison of the immune recognition potential of the neoantigens in actinic keratosis and cutaneous squamous cell carcinoma samples. The fitness cost was subsequently adjusted by the expression rates of the neoantigens to examine the role of neoantigen expression in tumor immune evasion. Our analyses indicate that, while the number of mutations and neoantigens are not significantly different between actinic keratoses and cutaneous squamous cell carcinomas, the predicted immune recognition of the neoantigen with the highest expression-adjusted fitness cost is lower for cutaneous squamous cell carcinomas compared with actinic keratoses. These findings suggest a role for the down-regulation of expression of highly immunogenic neoantigens in the immune escape of cutaneous squamous cell carcinomas. Furthermore, these findings highlight the importance of incorporating additional factors, such as the quality and expression of the neoantigens, rather than focusing solely on tumor mutational burden, in assessing immune recognition potential.

Highlights

In the Medicare fee-for-service population, there were over one million cutaneous squamous cell carcinomas diagnosed in 2012 in the United States, and the incidence is increasing [1]
These data show that neoantigens predicted to bind MHC class I are present in both Actinic keratoses (AKs) and cutaneous squamous cell carcinomas (cuSCCs) samples
Given that a low percentage of AKs progress to cuSCCs, it is important to understand what allows some of these precursor lesions to escape immune surveillance and become invasive cuSCC, while others AKs remain in equilibrium or are eliminated

Summary

Introduction

In the Medicare fee-for-service population, there were over one million cutaneous squamous cell carcinomas (cuSCCs) diagnosed in 2012 in the United States, and the incidence is increasing [1]. Actinic keratoses (AKs) are generally considered to result from cumulative ultra-violet light-induced DNA mutations, and a small percentage of these precursor lesions progress to invasive cuSCC over time [5]. Mutations in the tumor cells generate neoantigens which may be recognized by the naturallyoccurring or therapeutically-induced immune response, and the immune response modulates tumor development. The immune system destroys the developing tumor before the tumor becomes clinically apparent. The elimination phase can result in complete elimination or residual cancer cell variants that resist elimination and enter the equilibrium phase. Tumor cell variants that are no longer recognized by the immune system enter the escape phase and manifest as clinically apparent tumors. Tumors with intact MHC class I had a significant decrease in expressed neoantigens compared with non-neoantigenic, somatic mutations, and only tumors with intact MHC class I and immune cell infiltration exhibited a decrease in expressed neoantigens [7]

Methods

Results

Conclusion