Expression of immune checkpoint ligands (ICLs) is necessary to trigger the inhibitory signal via immune checkpoint receptors (ICRs) in exhausted T cells under tumor immune microenvironment. Nevertheless,to our knowledge, ICL expression profile in cancer patients has not been investigated. Using previously reported RNA-seq data sets, we found that expression of ICLs was patient specific but their coexpression can be patterned in non–small-cell lung cancers (NSCLCs). Since the expression of PD-L1 and poliovirus receptor (PVR) among various ICLs was independently regulated, we could stratify the patients who were treated with anti–PD-1 later into 4 groups according to the expression level of PD-L1 and PVR. Of interest, high PVR and low PVR expressions in PDL1–expressing patients enriched nonresponders and responders to PD-1 blockade, respectively, helping in further selection of responders. Using a genetically engineered cancer model, we also found that PVR-deficient and PD-L1–sufficient tumor-bearing mice were highly sensitive to anti–PD-1 therapy, whereas PVR-sufficient and PD-L1–deficient tumor-bearing mice were resistant to anti–PD-1 therapy. Taken together, our study provides a concept that combinatorial expression patterns of PVR and PD-L1 are key determinants for PD-1 blockade and furthermore suggest a better therapeutic usage of immune checkpoint blockades (ICBs).
Bibliographical noteFunding Information:
We wish to thank S.W. Lee at POSTECH for providing MC38 cell line. We also thank I. Choi at Inje University for providing PD-L1–KO mice. We thank E.C. Shin and S.H. Park at KAIST for helpful discussion and useful comments with overall formatting of manuscript. We thank Flow Cytometry Core for help with establishing engineered cancer cell lines. This study was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (2018R1A2A1A05076997 and 2017R1A5A1014560 to SJH; 2017R1D1A1B03029874, 2019M3A9B6065231, and 2017M3A9E9072669 to HRK) and the Institute for Basic Science (IBS-R013-A1 to DH). This study was also supported by a grant from Ministry of Food and Drug Safety (18182MFDS408 to SJH) and KBRI basic research program through Korea Brain Research Institute funded by Korean MSIT (19-BR-03-02 to SHC). BRL, JM, MJK, and BL are fellowship awardee by BK21 PLUS program.
Copyright: © 2020, American Society for Clinical Investigation.
All Science Journal Classification (ASJC) codes