Programmed Death 1 Ligand Expression in the Monocytes of Patients with Hepatocellular Carcinoma Depends on Tumor Progression

Abstract

Monocytes (CD14+ cells) from advanced-stage hepatocellular carcinoma (HCC) patients express programmed death 1 ligand (PD-L)/PD-1 and suppress the host antitumor immune response. However, it is unclear whether cancer progression is associated with CD14+ cells. We compared CD14+ cell properties before and after cancer progression in the same HCC patients and examined their role in antitumor immunity. CD14+ cells were isolated from 15 naïve early-stage HCC patients before treatment initiation and after cancer progression to advanced stages. Although CD14+ cells from patients at early HCC stages exhibited antitumor activity in humanized murine chimera, CD14+ cells from the same patients after progression to advanced stages lacked this activity. Moreover, CD14+ cells from early HCC stages scantly expressed PD-L1 and PD-L2 and produced few cytokines, while CD14+ cells from advanced stages showed increased PD-L expression and produced IL-10 and CCL1. CD14+ cells were also isolated from five naïve advanced-stage HCC patients before treatment as well as after treatment-induced tumor regression. The CD14+ cells from patients with advanced-stage HCC expressed PD-L expressions, produced IL-10 and CCL1, and exhibited minimal tumoricidal activity. After treatment-induced tumor regression, CD14+ cells from the same patients did not express PD-Ls, failed to produce cytokines, and recovered tumoricidal activity. These results indicate that PD-L expression as well as CD14+ cell phenotype depend on the tumor stage in HCC patients. PD-L expressions of monocytes may be used as a new marker in the classification of cancer progression in HCC.

The liver cancer immune microenvironment: Therapeutic implications for hepatocellular carcinoma

“…These PD-L1/2 + CD14 + monocytes also expressed immunesuppressive cytokines such as IL-10 and CCL1. [71] Tumor-educated CCR1 + CD14 + monocytes express PD-L1, B7-H3, and TIM3, and upregulate tolerogenic metabolic enzymes, promoting angiogenesis and metastasis. [72] Analysis of chemokine expression in HCC cell lines and tissues identified CCL15 as a main recruiter of this CCR1 + CD14 + subset to the tumor invasive margin, [72] and in two cohorts of patients (n = 360 and n = 253), those with high CCL15 levels had a worse prognosis.…”

“…Finally, the overall survival of patients with PD‐L1/2 + CD14 + monocytes was shorter than those with other CD14 + cells ( n = 87). These PD‐L1/2 + CD14 + monocytes also expressed immune‐suppressive cytokines such as IL‐10 and CCL1 71. Tumor‐educated CCR1 + CD14 + monocytes express PD‐L1, B7‐H3, and TIM3, and upregulate tolerogenic metabolic enzymes, promoting angiogenesis and metastasis 72.…”

The Dynamic Change of Immune Checkpoints and CD14+ Monocytes in Latent Tuberculosis Infection

“…This finding might suggest that CD14+ monocytes would be primed for Mtb defense in the LTBI stage because alveolar macrophages cannot kill Mtb after phagocytosis [20] due to an evasion mechanism in the LTBI host. On the monocytes, PD-L1 and PD-L2 tend to decrease to help increase the immunity of CD14+ monocytes [13]. For clinical practice, if IGRA is a borderline value for LTBI, CD14+ monocytes for LTBI without renal impairment and PD-L2+CD14+ monocytes plus TIM3+ monocytes in LTBI with ESRD could be helpful because negative conversion is not uncommon [26].…”

“…Males were more predominant in the LTBI-ESRD group than in the LTBI-non-CKD group (71.8% vs. 47.4%, p = 0.019). There were more smokers in LTBI-ALL group (13,22.4%) than HC group (3, 10.3%), who mostly were subjects with hemodialysis (12, 30.8%). The co-morbidities and radiologic findings on prior TB were not different in these three groups.…”

“…Classical monocytes in the blood with CD14+ expression are the major sources of alveolar macrophages, and they can provide antigen presentation and help phagocytosis [12]. In addition, the PD-1 ligands 1 and 2 (PD-L1 and 2) may regulate the function of monocytes [13,14] and affect the tolerance of innate immunity to LTBI. However, the above-mentioned immune checkpoints and associated pathways have never been studied in LTBI.…”