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1. KRAS-Driven Lung Adenocarcinoma and B Cell Infiltration: Novel Insights for Immunotherapy

Author

Daniela Petriella, Gabriella Del Bene, Rosamaria Pinto, Simona De Summa, Annamaria Catino, Pamela Pizzutilo, Francesco Alfredo Zito, Rosanna Lacalamita, Antonia Zonno, Stefania Tommasi, Michele Montrone, and Maria Antonietta Botticella

Subjects
0301 basic medicine, LUAD, Cancer Research, In silico, medicine.medical_treatment, Biology, medicine.disease_cause, Malignancy, lcsh:RC254-282, Article, 03 medical and health sciences, 0302 clinical medicine, medicine, KRAS, tumor microenvironment, Lung cancer, B cell, Tumor microenvironment, B cells, Immunotherapy, medicine.disease, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, 030104 developmental biology, medicine.anatomical_structure, Oncology, 030220 oncology & carcinogenesis, Cancer research, Adenocarcinoma, immunotherapy
Abstract

Non-small-cell lung cancer, histologically classified into adenocarcinoma (AD) and squamous cell carcinoma, is one of the most deadly malignancies worldwide. Lung AD (LUAD) could benefit of a plethora of target therapies and, in the last few years, also of immunotherapies. Here we focused on a real-life cohort of LUAD and The Cancer Genome Atlas (TCGA)-LUAD dataset aiming to gain insights into the immune contexture of such a malignancy. We explored the mutational status of 41 genes and the expression of 94 genes, related to immune-checkpoint, inflammation, and stromal microenvironment. Surprisingly, we found that our cohort has a very low mutational burden if we consider our panel as its surrogate. Regarding gene expression data, we identified 31 genes significantly deregulated in tumor tissues compared with a pool of normal samples. Unsupervised hierarchical clustering of the deregulated genes is able to identify two clusters of tumor samples, differently enriched in alterations in actionable genes. In particular, we identified a cluster enriched in patients carrying KRAS alterations. In silico deconvolution, that is the inferring of tumor microenvironment composition by gene expression data, through TIMER algorithm has been performed to explore immune microenvironment. Estimation performed on our gene expression matrix showed that B cell infiltration is lower in the KRAS-mutated enriched cluster, as in the TCGA-LUAD dataset. Such a finding has been validated in situ through immunohistochemistry in an independent cohort. Moreover, cases in LUAD-TCGA with low B cell infiltration have a significantly worse overall survival than those with higher levels. In the real-life cohort we observed that cases belonging to cluster enriched in KRAS-mutated patients have a poor outcome. LUAD driven by KRAS mutation represents an unmet clinical need, being refractory to pharmacological inhibition. Our results link KRAS mutations to B cell infiltration. Thus, the present findings could be helpful in a better definition of immunotherapeutic approaches for KRAS mutated patients.

Published
2019

2. KRAS-Driven Lung Adenocarcinoma and B Cell Infiltration: Novel Insights for Immunotherapy.

Author

Rosamaria, Pinto, Daniela, Petriella, Rosanna, Lacalamita, Michele, Montrone, Annamaria, Catino, Pamela, Pizzutilo, Antonietta, Botticella Maria, Alfredo, Zito Francesco, Gabriella, Del Bene, Antonia, Zonno, Stefania, Tommasi, and Simona, De Summa

Subjects
ADENOCARCINOMA, B cells, BIOMARKERS, CANCER patients, CELL lines, GENE expression, IMMUNOHISTOCHEMISTRY, IMMUNOTHERAPY, INFLAMMATION, LUNG cancer, LUNG tumors, GENETIC mutation, SURVIVAL, TUMORS
Abstract

Non-small-cell lung cancer, histologically classified into adenocarcinoma (AD) and squamous cell carcinoma, is one of the most deadly malignancies worldwide. Lung AD (LUAD) could benefit of a plethora of target therapies and, in the last few years, also of immunotherapies. Here we focused on a real-life cohort of LUAD and The Cancer Genome Atlas (TCGA)-LUAD dataset aiming to gain insights into the immune contexture of such a malignancy. We explored the mutational status of 41 genes and the expression of 94 genes, related to immune-checkpoint, inflammation, and stromal microenvironment. Surprisingly, we found that our cohort has a very low mutational burden if we consider our panel as its surrogate. Regarding gene expression data, we identified 31 genes significantly deregulated in tumor tissues compared with a pool of normal samples. Unsupervised hierarchical clustering of the deregulated genes is able to identify two clusters of tumor samples, differently enriched in alterations in actionable genes. In particular, we identified a cluster enriched in patients carrying KRAS alterations. In silico deconvolution, that is the inferring of tumor microenvironment composition by gene expression data, through TIMER algorithm has been performed to explore immune microenvironment. Estimation performed on our gene expression matrix showed that B cell infiltration is lower in the KRAS-mutated enriched cluster, as in the TCGA-LUAD dataset. Such a finding has been validated in situ through immunohistochemistry in an independent cohort. Moreover, cases in LUAD-TCGA with low B cell infiltration have a significantly worse overall survival than those with higher levels. In the real-life cohort we observed that cases belonging to cluster enriched in KRAS-mutated patients have a poor outcome. LUAD driven by KRAS mutation represents an unmet clinical need, being refractory to pharmacological inhibition. Our results link KRAS mutations to B cell infiltration. Thus, the present findings could be helpful in a better definition of immunotherapeutic approaches for KRAS mutated patients. [ABSTRACT FROM AUTHOR]

Published
2019
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