PD-1-Positive Tumor-Associated Macrophages Define Poor Clinical Outcomes in Patients With Muscle Invasive Bladder Cancer Through Potential CD68/PD-1 Complex Interactions.

Li-Ren Jiang,Guo-Hui Fu,Yong-Hua Liu,Ya-Qin Han,Dong-Yun Mu,Ji-Ji Yang,Si-Teng Chen,Xiao-Qin Shi,Jin He,Ning Zhang,Feng Gao

doi:10.3389/fonc.2021.679928

Abstract

Tumor-associated macrophages (TAMs) regulate tumor immunity. Previous studies have shown that the programmed cell death protein 1 (PD-1)-positive TAMs have an M2 macrophage phenotype. CD68 is a biomarker of TAMs and is considered to be a poor prognostic marker of several malignancies. Our results show that PD-1-positive TAMs can be a negative survival indicator in patients with muscle-invasive bladder cancer (MIBC), and that the mechanistic effects could result due to a combination of PD-1 and CD68 activity. We analyzed 22 immune cell types using data from 402 patients with MIBC from the TCGA database, and found that a high immune score and M2 TAMs were strongly associated with poor clinical outcomes in patients with MIBC. Further, we analyzed resected samples from 120 patients with MIBC and found that individuals with PD-1-positive TAMs showed a reduction in 5-year overall survival and disease-free survival. Additionally, PD-1-positive TAMs showed a significant association with higher programmed death-ligand 1 (PD-L1) expression, the Ki67 index, the pT stage and fewer CD8-positive T cells. Through the co-immunoprecipitation (co-IP) assay of THP-1 derived macrophages, we found that CD68 can bind to PD-1. The binding of CD68 and PD-1 can induce M2 polarization of THP-1 derived macrophages and promote cancer growth. The anti-CD68 treatment combined with peripheral blood mononuclear cells (PBMC) showed obvious synergy effects on inhibiting the proliferation of T24 cells. Together, these results indicate for the first time that CD68/PD-1 may be a novel target for the prognosis of patients with MIBC.

Highlights

Bladder cancer is the most common cancer of the urinary system that results in malignancies, and the resulting tumor types can be classified into non-muscle invasive bladder cancer (NMIBC) and muscle-invasive bladder cancer (MIBC) [1,2,3]
PD-1/programmed death-ligand 1 (PD-L1) related immunotherapy for bladder cancer, especially for patients with MIBC, is still improvable [5], as these are effective in only a certain proportion of patients with bladder cancer [26]
This study is the first to demonstrate that CD68 can bind to PD-1, which may provide a new target for future immunotherapeutic strategies

Summary

Introduction

Bladder cancer is the most common cancer of the urinary system that results in malignancies, and the resulting tumor types can be classified into non-muscle invasive bladder cancer (NMIBC) and muscle-invasive bladder cancer (MIBC) [1,2,3]. Cisplatin is a first-line drug for the treatment of metastatic MIBC [4, 5]. There are no approved second-line drugs for patients with MIBC who show a relapse after cisplatin treatment; immunotherapy-related drugs can fill this gap [6]. The use of PD-1/PD-L1 inhibitors has set a new paradigm for the treatment of patients with metastatic bladder cancer, and who are ineligible and resistant for cisplatin-based therapy [7]. ~10% of patients with bladder cancer treated with PD-1/PD-L1 inhibitors show rapid progression of the disease, known as hyper-progressive disease [8]. The mechanisms underlying the effects of these immunotherapeutic inhibitors are unclear and require further investigation

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