Therapies targeting immune checkpoints have recently shown promising activity in non-small cell lung cancer (NSCLC) patients. T-cell activation is controlled by the balance of co-stimulatory molecules and co-inhibitory molecules (immune checkpoint molecules).
A comprehensive analysis was performed for immune profiles of tumor microenvironment in NSCLCs using cap analysis of gene expression (CAGE). CAGE is a method used to quantify promoter activities across the whole genome by determining the 5’ ends of capped RNA molecules with next-generation sequencing. Gene expressions of PD-L1, PD-L2, co-inhibitory molecules (CTLA-4, PD-1, TIM-3, BTLA, VISTA, and LAG-3), co-stimulatory molecules (CD28, OX40, GITR, CD317, CD27, and HVEM), and markers of immune cells (CD4, CD8, CD25, Foxp3, CD68, and CD204) were quantified using RNA extracted from frozen tumor tissue samples of 100 surgically resected NSCLCs (71 adenocarcinomas (AD), 22 squamous cell carcinomas (SQ), and 7 other histologic types).
NSCLCs in this study were classified into two groups: tumors with high expression of almost all immunomodulatory targets (immunoreactive) and tumors with intermediate or low expression (non-immunoreactive). Co-stimulatory and co-inhibitory molecules were simultaneously highly expressed in immunoreactive tumors. The prognosis of immunoreactive ADs was worse than that of non-immunoreactive ADs regardless of histologic grade or EGFR mutation status (P = 0.002). However, an opposite trend was observed in SQs (P = 0.789). In ADs, high expression of CD137, TIM-3, and HVEM was an unfavorable prognostic factor. In SQs, high expression of CTLA-4 and LAG-3 was a favorable prognostic factor, and whereas HVEM expression was unfavorable.
NSCLCs can be classified into immunogenic and non-immunogenic tumors. The prognostic effect of immunomodulatory molecules differs according to histologic types and gene expression profiles of immune cells.
Clinical trial identification
Legal entity responsible for the study
Juntendo University School of Medicine.
Has not received any funding.
All authors have declared no conflicts of interest.