Cancer immunogenomic approach to neoantigen discovery in a checkpoint blockade responsive murine model of oral cavity squamous cell carcinoma.

Maxim Artyomov,Tianxiang Lin,Ravindra Uppaluri,Liye Zhou,Lan Nguyen,Robert D Schreiber,Gavin P Dunn,Dariusz Przybylski,Paul Zolkind,Alexander P Miceli,Anton Alexandrov,Nemanja Marjanovic,Tanner Johanns,Clint T Allen

doi:10.18632/oncotarget.23751

Abstract

Head and neck squamous cell carcinomas (HNSCC) are an ideal immunotherapy target due to their high mutation burden and frequent infiltration with lymphocytes. Preclinical models to investigate targeted and combination therapies as well as defining biomarkers to guide treatment represent an important need in the field. Immunogenomics approaches have illuminated the role of mutation-derived tumor neoantigens as potential biomarkers of response to checkpoint blockade as well as representing therapeutic vaccines. Here, we aimed to define a platform for checkpoint and other immunotherapy studies using syngeneic HNSCC cell line models (MOC2 and MOC22), and evaluated the association between mutation burden, predicted neoantigen landscape, infiltrating T cell populations and responsiveness of tumors to anti-PD1 therapy. We defined dramatic hematopoietic cell transcriptomic alterations in the MOC22 anti-PD1 responsive model in both tumor and draining lymph nodes. Using a cancer immunogenomics pipeline and validation with ELISPOT and tetramer analysis, we identified the H-2Kb-restricted ICAM1P315L (mICAM1) as a neoantigen in MOC22. Finally, we demonstrated that mICAM1 vaccination was able to protect against MOC22 tumor development defining mICAM1 as a bona fide neoantigen. Together these data define a pre-clinical HNSCC model system that provides a foundation for future investigations into combination and novel therapeutics.

Highlights

Despite advances in surgical techniques, chemotherapeutics and targeted radiation therapy, oral cavity squamous cell carcinoma (OSCC) remains a treatment challenge and still carries a 60% 5-year survival rate [1]
To identify an immunogenic preclinical model of OSCC, we investigated the response to checkpoint blockade of two syngeneic tumor cell lines — MOC2 and MOC22 — which grow progressively in wild-type C57BL/6 mice
Whereas MOC22 harbored a significant increase in CD8+ T cell infiltration with anti-PD1 treatment (p=0.0195), no difference in the CD8+ T cell population was observed in MOC2 following checkpoint blockade treatment (p=0.2924) (Figure 1C)

Summary

Introduction

Despite advances in surgical techniques, chemotherapeutics and targeted radiation therapy, oral cavity squamous cell carcinoma (OSCC) remains a treatment challenge and still carries a 60% 5-year survival rate [1]. At least in part, to the lack of robust sensitivity of OSCC to adjuvant therapies [2, 3]. To address this need for novel therapeutic modalities, significant efforts have been directed at better understanding the biology of these tumors to identify targeted treatment approaches. Recent work to characterize the genomic landscape of head and neck squamous cell carcinomas (HNSCC) by the TCGA and others demonstrated that the majority of these tumors do not possess actionable mutations for targeted therapy [4]. The response rates to anti-PD1 mAbs in these trials were 13.3% [8] and 20% [7], and the failure to meet endpoints in a pembrolizumab Phase III clinical trial [9] together indicate the need for improved biomarkers to predict and monitor responsiveness to checkpoint inhibition

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Conclusion