CMTM6, the newly identified PD-L1 regulator, correlates with PD-L1 expression in lung cancers

Feng Gao,Jing Chen,Jia Wang,Peixiang Li,Sheng Wu,Jue Wang,Yong Ji

doi:10.1016/j.bbrep.2019.100690

Abstract

Modulation of Immune check point regulators, especially the PD-1/PD-L1 axis, plays a critical role in successful management of a small proportion of lung cancer patients, but not so effective in the rest of lung cancer patients. A better understanding of immunotherapy non-responsive or resistant patients therefore warranted for future development of novel therapeutics. The newly identified regulator CMTM6 (CKLF-like MARVEL transmembrane domain containing 6) has been reported to serves as the stabilizer of PD-L1 and enhances the inhibitory effect of PD-L1 on immune system in both cell line and animal models, but its clinical relevance associated with PD-L1 is unknown and the current study is designed to address this question. The study using immunohistochemistry demonstrated that CMTM6 positivity from 15 out of 19 types of cancers with our in-house tissue microarray, and PD-L1 expression is always found only in CMTM6 positive cancers. CMTM6 and PD-L1 expression were analyzed in 81 lung cancer patient sample, and we observed that CMTM6 expression correlated with cancer histotypes and inversely correlated with cancer metastases, but not with patients’ age and gender. No PD-L1 expression was observed in negative CMTM6 samples. Higher expression PD-L1 is also associated with higher CMTM6 expression. In summary, CMTM6 expression is associated with PD-L1 expression, as well as lung cancer histotypes and metastasis. The results thus for the first time confirmed earlier reports on CMTM6/PD-L1 connection, from a clinical aspect of analysis.

Highlights

The identification of the Programmed Cell Death – 1/Ligand 1 (PD1/PD-L1) immune checkpoint pathway has shown great promise as a therapeutic target to elicit immune response against cancer cells [1]
PD-L1 expression was present with 12 samples (28.5%) from 8 types of cancers, while negative with the other 11 types of cancers (Table 1), PD-L1 positive samples are all positive with CMTM6 expression, none of CMTM6 negative samples have positivity for PD-L1 expression
After the observation of the expression of CMTM6 and PD-L1 in different types of cancers, we focused the rest of our study on lung cancers as PD-1/PD-L1 inhibitors are currently in the first line therapy for lung cancers

Summary

Introduction

The identification of the Programmed Cell Death – 1/Ligand 1 (PD1/PD-L1) immune checkpoint pathway has shown great promise as a therapeutic target to elicit immune response against cancer cells [1]. The PD-1 protein is a receptor expressed on the surface of T cells, B cells and macrophages that delivers co-inhibitory signal, playing a critical role in maintaining peripheral tolerance and preventing autoimmunity [2,3]. This co-inhibitory signal, is delivered only when PD-L1 is bound to PD-1. Though being essential under physiological condition to prevent autoimmunity, PD-1/PD-L1 pathway is in the same way exploited by cancer cells with increased PD-L1 expression to inhibit the immune response and to evade successfully host immune surveillance

Methods

Results

Conclusion