Tumor-Activated Monocytes Promote Expansion of IL-17–Producing CD8+ T Cells in Hepatocellular Carcinoma Patients

Abstract

The proinflammatory IL-17–producing CD8+ T cells (Tc17 cells) have recently been detected in tumors, but the nature and regulation of these cells in human tumors are presently unknown. We have recently found that IL-17+ cells are accumulated in human hepatocellular carcinomas (HCC), where they promote disease progression by fostering angiogenesis. In this study, we showed that Tc17 cells constitute a remarkable portion of IL-17–producing cells in human HCC. Although most circulating Tc17 cells were negative for IFN-γ, >80% of Tc17 cells in HCC tissues were positive for IFN-γ, and they were enriched predominantly in invading tumor edge. Most CD68+ cells located in invading tumor edge exhibited an activated phenotype and, accordingly, the activated monocytes isolated from HCC tissues were significantly superior to those isolated from nontumor tissues in inducing expansion of Tc17 cells in vitro with phenotypic features similar to those isolated from tumors. Compared with IL-17−IFN-γ+CD8+ cells, these IFN-γ+Tc17 cells have significantly higher expression of proinflammatory cytokines (IL-2, IL-22, and TNF-α), but reduced expression of granzyme B and perforin. Moreover, we found that tumor-activated monocytes secreted a set of key cytokines (IL-1β, IL-6, and IL-23) to trigger the proliferation of Tc17 cells. These data reveal an intriguing mechanism in which human Tc17 cells are generated by a fine-tuned collaborative action between different types of immune cells in distinct tumor microenvironments.

The Multifaceted Roles Neutrophils Play in the Tumor Microenvironment

“…TAMs contribute to tumor growth and progression through extracellular matrix remodeling, promotion of tumor cell invasion and metastasis, angiogenesis, lymphangiogenesis and immune suppression [6]. TAMs may also secrete cytokines IL-1β, IL-6 and IL-23 that trigger the proliferation of IL-17-producing CD8 + Tc17 cells [54], a T cell subset that is often found to be present in various tumors [55]. IL-17 increases the synthesis of C-X-C chemokines from epithelial cells [56] leading to increased neutrophil infiltration into the tumor [57].…”

Heterogeneity in the Differentiation and Function of CD8+ T Cells

“…T cells, a subpopulation of adaptive lymphocytes, play an important role in immunity to intracellular pathogens and tumors (Gattinoni et al 2012;Klenerman and Hill 2005;Kuang et al 2010;Lu et al 2014). They also contribute to the regulation of pathologic processes such as autoimmune and allergic disorders (Huber et al 2009;Kim and Cantor 2011;Loser et al 2010;Tang et al 2012;Visekruna et al 2013).…”

“…In this setting, Tc17 cells seem to promote tumor progression (Kuang et al 2010). In contrast, in a mouse melanoma model, Tc17 cells enhance anti-tumor immunity, suggesting different functions of Tc17 cells depending on the tumor microenvironment (Hinrichs et al 2009).…”

Prognostic Significance of the Peripheral Blood Absolute Monocyte Count in Patients with Locally Advanced or Metastatic Hepatocellular Carcinoma Receiving Systemic Chemotherapy

“…A large body of studies have highlighted that a range of HCC-derived cytokines including chemokine ligand 2 and macrophage colonystimulating factor promote recruitment of peripheral blood monocytes into tumor microenvironment and subsequently differentiation into mature macrophages which are designated as tumor-associated macrophages (TAMs) (Benetti et al, 2008;Zhu et al, 2008;Takai et al, 2009). Furthermore, activated TAMs in turn establish a distinct inflammatory microenvironment responsible for stimulating proliferation, invasion, metastasis and angiogenesis of HCC (Peng et al, 2005;Schimanski et al, 2006;Liu et al, 2008;Kuang et al, 2010;Werno et al, 2010;Chen et al, 2012). It is reasonable to believe that the vicious circle between HCC and TAMs is the driving engine of HCC for its continuous deterioration.…”