Comprehensive Characterization of Human Lung Large Cell Carcinoma Identifies Transcriptomic Signatures with Potential
Javier Ramos-Paradas1,2, David Gómez-Sánchez1,2, Aranzazu Rosado1
1H12O-CNIO Lung Cancer Clinical Research Unit, Health Research Institute Hospital 12 de Octubre (imas12)/Spanish National Cancer Research Center (CNIO), 28041 Madrid, Spain.
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.
Insights
Lung large cell carcinoma (LCC) subgroups were identified based on molecular and immune features. This classification reveals biomarkers that may predict immunotherapy response in non-small cell lung cancer (NSCLC) patients.
Area of Science:
- Oncology
- Immunology
- Genomics
Background:
- Lung cancer is a leading cause of cancer mortality globally.
- Non-small cell lung cancer (NSCLC) is the most common type, with immunotherapy showing promise.
- Lung large cell carcinoma (LCC), a subtype of NSCLC, has poorly defined molecular and immune characteristics, hindering immunotherapy response prediction.
Purpose of the Study:
- To investigate the molecular and immune landscape of lung large cell carcinoma (LCC).
- To identify potential biomarkers for predicting immunotherapy response in LCC.
- To classify LCC into subgroups based on genotype-immunophenotype associations.
Main Methods:
- A cohort of 18 early-stage LCC cases was analyzed.
- Comprehensive molecular profiling included genomic and immune-targeted sequencing.
- Immunohistochemistry was used to assess immune cell populations.
Main Results:
- Unbiased clustering identified two novel LCC subgroups: pro-immunogenic and pro-tumorigenic.
- Pro-immunogenic tumors exhibited specific molecular alterations, increased immune infiltration, and upregulated immune-response genes.
- Pro-tumorigenic tumors were associated with tumoral progression.
Conclusions:
- The study identified distinct molecular and immune subgroups within LCC.
- A set of potential biomarkers for predicting immunotherapy response in LCC was discovered.
- These findings could enhance patient selection for immunotherapy in NSCLC.
