J. M. Obeid1, G. Erdag4, R. D. Gentzler2, M. G. Brown5, J. V. Cross3, D. H. Deacon1, T. N. Bullock3, C. L. Slingluff1 1University Of Virginia,Surgery Department,Charlottesville, VA, USA 2University Of Virginia,Heme/Onc / Medicine Department,Charlottesville, VA, USA 3University Of Virginia,Pathology Department,Charlottesville, VA, USA 4Johns Hopkins University School Of Medicine,Pathology Department,Baltimore, MD, USA 5University Of Virginia,Immunology,Charlottesville, VA, USA
Introduction: Expression of PD-L1 on tumor cells reflects the presence of an active immune response, and its increased expression is associated with improved patient survival in several cancers. In Non-small cell lung cancer (NSCLC), however, this association is less clear. Effective immune responses may be inhibited in the tumor microenvironment by downregulating class I MHC (MHC-I) expression on cancer cells. Thus, we hypothesized that low MHC-I expression may add additional negative prognostic value in NSCLC with low PD-L1 expression.
Methods: A tissue microarray (TMA) was constructed from 151 NSCLC specimens (90 adenocarcinoma (AdCA), 58 squamous cell (SQCC), 3 mixed histology). Patients had stage I (61%), II (22%), III (14%) and IV (3%) disease that was resected between 2011 and 2014 (median follow up: 27 months). The TMA was analyzed by immunohistochemistry for PD-L1 (clone 5H1) and MHC-I heavy chains (clone HC-10). PD-L1 expression was assessed as a percentage of cancer cells staining positive, with 5% and 50% thresholds for positivity. Expression of the MHC-I was reported as a score of 1 to 5, accounting for staining intensity and percent of tumor cells staining. Kaplan Meier curves were used to plot survival, and a log rank test was used to test associations with patient survival.
Results: Low PD-L1 expression, below a 5% threshold, was associated with worse overall survival (p=0.02) but the association was not significant with a 50% threshold (p=0.06). Low MHC-I expression on tumor cells (score ≤ 3) was not significantly associated with worse survival (p=0.14). However, when combined, the tumors with both low MHC-I and low PD-L1 expression (<5% and <50%) were significantly associated with worse patient outcomes (p=0.002 (Figure) and p=0.004 respectively), similar results were obtained in SQCC and AdCA subsets separately, and when controlling for stage.
Conclusion: Co-occurrence of low PD-L1 expression and MHC-I downregulation in tumor cells, is associated with a significant decrease in patient survival for patients with NSCLC. When MHC-I expression is high, PD-L1 expression loses its prognostic significance. This finding may help to clarify the role of pre-existing immunity to NSCLC, and may help to develop a useful biomarker combination. By characterizing the immune profile of NSCLC, modifications of this analysis should be explored for their ability to predict patient response to immune therapy.
