Comprehensive Characterization of Human Lung Large Cell Carcinoma Identifies Transcriptomic Signatures with Potential Implications in Response to Immunotherapy.

Javier Ramos-Paradas,Jon Zugazagoitia,Nuria Carrizo,Esther Conde,Eva M Garrido-Martin,Ricardo García-Luján,Ana B Enguita,Alvaro C Ucero,David Gómez-Sánchez,Luis Paz-Ares,Irene Ferrer,Aranzazu Rosado

doi:10.3390/jcm11061500

Abstract

Lung cancer is the leading cause of cancer mortality worldwide, with non-small cell lung cancer (NSCLC) being the most prevalent histology. While immunotherapy with checkpoint inhibitors has shown outstanding results in NSCLC, the precise identification of responders remains a major challenge. Most studies attempting to overcome this handicap have focused on adenocarcinomas or squamous cell carcinomas. Among NSCLC subtypes, the molecular and immune characteristics of lung large cell carcinoma (LCC), which represents 10% of NSCLC cases, are not well defined. We hypothesized that specific molecular aberrations may impact the immune microenvironment in LCC and, consequently, the response to immunotherapy. To that end, it is particularly relevant to thoroughly describe the molecular genotype–immunophenotype association in LCC–to identify robust predictive biomarkers and improve potential benefits from immunotherapy. We established a cohort of 18 early-stage, clinically annotated, LCC cases. Their molecular and immune features were comprehensively characterized by genomic and immune-targeted sequencing panels along with immunohistochemistry of immune cell populations. Unbiased clustering defined two novel subgroups of LCC. Pro-immunogenic tumors accumulated certain molecular alterations, showed higher immune infiltration and upregulated genes involved in potentiating immune responses when compared to pro-tumorigenic samples, which favored tumoral progression. This classification identified a set of biomarkers that could potentially predict response to immunotherapy. These results could improve patient selection and expand potential benefits from immunotherapy.

Highlights

Lung cancer is responsible for the second highest incidence of tumors worldwide, representing 11.4% of newly diagnosed cancer cases in 2020
Samples were required to fulfill the following criteria in order to be eligible for the study: large cell carcinoma (LCC) histology, early stage, sufficient sample availability, complete clinical annotation and agreed consent provided by the patient for further analyses to be performed
It is important to emphasize that all these genetic alterations were of uncertain significance in our bioinformatic analysis with the Varsome database, with the exception of a G12C mutation in KRAS, which may lead to treatment adaptation, considering the new KRAS inhibitors under investigation [47]

Summary

Introduction

Lung cancer is responsible for the second highest incidence of tumors worldwide, representing 11.4% of newly diagnosed cancer cases in 2020. It is the leading cause of cancer-related deaths, accounting for 20% of the total [1]. 15% of all lung cancer cases, and non-small cell lung cancer (NSCLC) which accounts for the remaining 85% of cases. This NSCLC subtype can subsequently be subdivided into the categories of adenocarcinoma (ADC), squamous cell carcinoma (SCC) and large cell carcinoma (LCC) [2], the latter of which is conventionally considered to represent around. This vague definition encompasses a broad and heterogeneous set of lung tumors, thereby complicating patient classification [4,5] and limiting scientific advances in the development of diagnostic and treatment strategies

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