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

Rosamaria Pinto¹, Daniela Petriella¹, Rosanna Lacalamita¹

¹Molecular Diagnostics and Pharmacogenetics Unit, IRCCS-Istituto Tumori "Giovanni Paolo II", VialeOrazioFlacco 65, 70124 Bari (BA), Italy.

|August 14, 2019

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.

Insights

KRAS mutations in lung adenocarcinoma (LUAD) are linked to reduced B cell infiltration and poorer outcomes. This suggests new immunotherapy strategies may be needed for KRAS-mutated LUAD patients.

Area of Science:

Oncology
Immunology
Genomics

Background:

Non-small-cell lung cancer (NSCLC), including lung adenocarcinoma (LUAD), is a leading cause of cancer mortality worldwide.
LUAD can be treated with targeted therapies and immunotherapies, but understanding its immune microenvironment is crucial for optimizing treatment.
KRAS mutations are common in LUAD and often associated with poor prognosis and resistance to therapies.

Purpose of the Study:

To investigate the immune contexture of LUAD by analyzing gene expression and mutational status in a real-world cohort and The Cancer Genome Atlas (TCGA) dataset.
To identify potential associations between specific genetic alterations, such as KRAS mutations, and the tumor immune microenvironment.
To explore the clinical implications of these findings for LUAD patient outcomes and immunotherapy strategies.

Main Methods:

Analysis of mutational status (41 genes) and gene expression (94 genes) in LUAD tumor tissues and normal samples.
Unsupervised hierarchical clustering to identify LUAD subtypes based on deregulated gene expression.
In silico deconvolution using the TIMER algorithm to assess immune cell infiltration.
Immunohistochemistry validation in an independent LUAD cohort.

Main Results:

A subset of LUAD patients was identified with a cluster enriched in KRAS alterations.
KRAS-mutated LUAD samples showed significantly lower B cell infiltration compared to non-mutated samples, confirmed by in silico and in situ analyses.
Lower B cell infiltration in LUAD was associated with significantly worse overall survival.
Patients in the KRAS-mutated enriched cluster exhibited a poor clinical outcome.

Conclusions:

KRAS mutations in LUAD are associated with a distinct immune microenvironment characterized by reduced B cell infiltration.
The findings highlight KRAS-mutated LUAD as an unmet clinical need, particularly concerning its refractoriness to current therapies.
This research provides a basis for developing novel immunotherapeutic approaches tailored to KRAS-mutated LUAD patients.

Read full analysis

Keywords:

B cells KRAS LUAD immunotherapy tumor microenvironment

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