Immune infiltration in tumor and adjacent non-neoplastic regions co-determines patient clinical outcomes in early-stage lung cancer

In recent years, the fraction of non-small cell lung cancer (NSCLC) patients diagnosed at an early stage has been increasing continuously. In this study we analyzed samples and data collected from 119 samples from 67 early-stage NSCLC patients, including 52 pairs of tumor and adjacent non-neoplastic samples, and performed RNA-seq analysis with high sequencing depth. We found that immune related genes were highly enriched among the differentially expressed genes and observed significantly higher inferred immune infiltration levels in adjacent non-neoplastic samples compared to the tumor samples. In survival analyses, the infiltration of certain immune cell types in tumor, but not adjacent non-neoplastic, samples were associated with overall patient survival, and excitingly, the differential infiltration between paired samples (tumor minus non-neoplastic) was more prognostic than expression in either non-neoplastic or tumor tissues. We also performed B cell receptor (BCR) and T cell receptor (TCR) repertoire analysis and observed more BCR/TCR clonotypes and increased BCR clonality in tumor than non-neoplastic samples. Finally, we carefully quantified the fraction of the 5 histological subtypes in our adenocarcinoma samples and found that higher histological pattern complexity was associated with higher immune infiltration and low TCR clonality in the tumor-proximal regions. In summary, our results indicated significantly differential immune characteristics between tumor and adjacent non-neoplastic samples and suggested the two regions provided complementary prognostic values in early-stage NSCLCs.