Transcriptomic Correlates of Immunologic Activation in Head and Neck and Cervical Cancer.

Cristina Saiz-Ladera,Juan J Cruz-Hernández,David Stewart,Mariona Baliu-Piqué,Alberto Ocana,Santiago Cabezas Camarero,Atanasio Pandiella,Gonzalo Fernández Hinojal,Pedro Pérez-Segura,Balázs Győrffy,Francisco J Cimas,Vanesa García-Barberán,Aránzazu Manzano

doi:10.3389/fonc.2021.714550

Abstract

Targeting the immune system has emerged as an effective therapeutic strategy for the treatment of various tumor types, including Head and Neck Squamous Cell Carcinoma (HNSCC) and Non-small-Cell Lung Cancer (NSCLC), and checkpoint inhibitors have shown to improve patient survival in these tumor types. Unfortunately, not all cancers respond to these agents, making it necessary to identify responsive tumors. Several biomarkers of response have been described and clinically tested. As of yet what seems to be clear is that a pre-activation state of the immune system is necessary for these agents to be efficient. In this study, using established transcriptomic signatures, we identified a group of gene combination associated with favorable outcome in HNSCC linked to a higher presence of immune effector cells. CD2, CD3D, CD3E, and CXCR6 combined gene expression is associated with improved outcome of HNSCC patients and an increase of infiltrating immune effector cells. This new signature also identifies a subset of cervical squamous cell carcinoma (CSCC) patients with favorable prognosis, who show an increased presence of immune effector cells in the tumor, which outcome shows similarities with the HP-positive HNSCC cohort of patients. In addition, CD2, CD3D, CD3E, and CXCR6 signature is able to predict the best favorable prognosis in terms of overall survival of CSSC patients. Of note, these findings were not reproduced in other squamous cell carcinomas like esophageal SCC or lung SCC. Prospective confirmatory studies should be employed to validate these findings.

Highlights

Squamous Cell Carcinoma (SCC) includes a wide range of tumors originated from diverse anatomical locations that share common molecular and genetic features [1]
The different gene signatures did not predict for better overall survival (OS) in comparison with some individual transcripts, with CD2 (HR=0.59; 95% confidence interval (CI)=0.45–0.77; log rank p= 7.5e−05), CD3D (HR=0.59; 95% CI=0.45–0.77; log rank p=0.0001), CD3E (HR=0.60; 95% CI=0.46–0.78; log rank p=0.00013), and CXCR6 (HR=0.59; 95% CI=0.45–0.78; log rank p=0.00023) (Table 2)
As the mutational burden has been associated with response to immune-modulatory drugs [18, 19], we explored if the expression of the identified immune signature CD2, CD3D, CD3E, CXCR6 was able to predict a better outcome in Head and Neck Squamous Cell Carcinoma (HNSCC) and in cervical squamous cell carcinoma (CSCC) with high mutational burden

Summary

Introduction

Squamous Cell Carcinoma (SCC) includes a wide range of tumors originated from diverse anatomical locations that share common molecular and genetic features [1]. SCCs are in many occasions incurable diseases in their advanced stages [1] This is the case for Head and Neck Squamous Cell Carcinoma (HNSCC) and Cervical Squamous Cell Carcinoma (CSCC), since the therapeutic options for both tumors, when diagnosed in the metastatic setting, are limited and outcome is severely compromised [3, 4]. Immunomodulators, immune checkpoint inhibitors like pembrolizumab or nivolumab, have shown to improve relapse-free survival (RFS) and overall survival (OS) [5,6,7,8] This has dramatically changed the expected survival of HNSCC patients, the metastatic setting, remained an incurable condition [9]. Expression of PD1 or PD-L1 or the presence of Tumor Infiltrating Lymphocytes (TIL) is associated with favorable survival, independently of the therapy administered, confirming the relevant role of the immune system in the antitumoral action [15, 16]

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