• Department of Internal Medicine, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital Zhengzhou, China.
• Duke Cancer Institute, Duke University Medical Center Durham, NC 27710, USA.
• Department of Biostatistics and Bioinformatics, Duke University School of Medicine Durham, NC 27710, USA.
• Department of Environmental Health and Epidemiology, Harvard School of Public Health Boston, MA 02115, USA.

Immunoregulatory interactions play a pivotal role in immune surveillance, recognition, and killing, particularly its internal pathway, likely playing an important role in immune escape. By using two genotyping datasets, one from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer screening trial (n = 1,185) as the discovery, and the other from Harvard Lung Cancer Susceptibility (HLCS) study (n = 984) as the validation, we evaluated associations between 4,713 genetic variants (338 genotyped and 4,375 imputed) in 60 genes involved in immunoregulatory interactions and survival of non-small cell lung cancer (NSCLC). We found that 115 SNPs were significantly associated with NSCLC overall survival in the discovery, of which four remained significant after validation by the HLCS dataset after multiple test correction by Bayesian false discovery probability. Final combined analysis identified two independent SNPs (KIR3DL2 rs4487030 A>G and PVR rs35385129 C>A) that predicted NSCLC survival with a combined hazards ratio of 0.84 (95% confidence interval = 0.76-0.93, P = 0.001) and 0.84 (95% confidence interval = 0.73-0.97, P = 0.021), respectively. Besides, expression quantitative trait loci analyses showed that these two survival-associated SNPs of KRI3DL2 and PVR were significantly associated with their mRNA expression levels in both normal lung tissues and whole blood cells. Additional analyses suggested an oncogenic role for KRI3DL2 and a suppressor role for PVR on the survival. Once further validated, genetic variants of KIR3DL2 and PVR may be potential prognostic markers for NSCLC survival.