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

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.

CIGB-300 Anticancer Peptide Differentially Interacts with CK2 Subunits and Regulates Specific Signaling Mediators in a Highly Sensitive Large Cell Lung Carcinoma Cell Model

“…Histological diagnosis of NSCLC is essential to accomplish an accurate treatment because the effectiveness of some therapeutic agents differ due to tumoral histology [4,7,8]. However, LCLC is one form of NSCLC that tends to grow more quickly and spread more aggressively than some other forms [9,10]. Furthermore, recent studies ratify that molecular screening must be taking into account in order to predict sensitivity for standard therapy [3].…”

“…Furthermore, up to 60% of lung adenocarcinoma and up to 50-80% of squamous cell carcinoma have a known targetable oncogenic driver mutation related with uncontrolled proliferation and cell survival [3,12]. However, the considerable percentage of patients, including those diagnosed with LCLC, remain an unmet medical need, and therefore the validation of new molecular targets is the main goal of many research groups [10,13].…”