Original contributionHigh transforming growth factor β expression represents an important prognostic parameter for surgically resected non–small cell lung cancer
Introduction
Non–small cell lung cancer (NSCLC) is the leading cause of cancer-related deaths, and despite strong therapeutic efforts, the prognosis has remained dismal, and new treatment strategies are needed [1]. The microenvironment of malignant tumors comprises a variety of different cell types (eg, tumor-associated fibroblasts, immune cells, endothelial cells) and locally produced cytokines, lipid mediators, and stromal components with essential protumor but also antitumor effects (Fig. 1). Because modern treatment strategies such as antiangiogenic compounds or immunomodulatory drugs also target stromal components, the tumor microenvironment is rapidly gaining importance. Thus, defining the exact role of each factor might help to discover new therapeutic targets and biomarkers predicting response to established therapies. The immune surveillance role of adoptive immune responses and the number of infiltrating immune cells and their distribution have been linked to prognosis [2]. Thereby, CD8+ cytotoxic T cells play a major role in preventing cancer development by destroying tumor cells in an antigen-specific manner. Granzyme B and T-cell–restricted intracellular antigen-1 (TIA-1) are localized in cytolytic granules and are important molecules for cancer cell destruction and represent markers of CD8+ cytotoxic T cells [3]. Transforming growth factor β (TGF-β) is among the most immunosuppressive cytokines and is produced by tumors and tumor-associated stromal cells, including regulatory T cells (Treg), fibroblasts, dendritic cells, and myeloid-derived suppressor cells [4]. It directly suppresses functions, migration, and expansion of innate (macrophages, natural killer cells) and adoptive (CD4+ helper cells and CD8+ cytotoxic cells) immune cells and can induce conventional CD4+ T cells to acquire properties of Treg, which suppress immune responses [4]. Mast cells have also been shown to induce Treg via TGF-β [5]. Mast cells can be found in the tumor microenvironment, and increasing numbers correlate with increased intratumor microvessel density, enhanced tumor growth, tumor invasion, and poor clinical outcome [6]. In addition to classical cytokines, chemokines critically regulate the cellular composition of the tumor microenvironment. CXCL12, also known as stromal cell–derived factor 1 (SDF-1), is known to exert anti-inflammatory functions and is mainly expressed by stromal cells via its cognate receptor CXCR4. SDF-1 has also been described to be secreted by tumor cells [7]. Treg express high levels of CXCR4, which can be induced by interleukin-2 and which might be involved in SDF-1–induced recruitment of Treg to the tumor [8]. Programed death 1 (PD-1) is a member of the CD28 costimulatory receptor superfamily expressed on a subset of thymocytes and up-regulated on activated T, B, and myeloid cells [9]. PD-1 inhibits T-cell activity by functioning as a negative regulator of the immune system, and high PD-1 expression has been associated with poor outcome in malignant neoplasms [9], [10].
In addition to secreted or membrane-anchored immunomodifying molecules, intracellular regulators of immune cell activation might also be of critical importance for tumor immunology. Casitas B-cell lymphoma-b (Cbl-b) is an E3 ubiquitin ligase that limits antigen responsiveness in T cells by targeting T-cell receptor–inducible signaling molecules. Cbl-b deficiency renders T cells hyperresponsive to antigenic stimulation independent of costimulation via CD28 and resistant to TGF-β.
We aimed to perform a comprehensive analysis of these various cellular components of the adoptive immune system and immune-modulating molecules in a large cohort of surgically resected samples with NSCLC to receive more detailed insight into the importance of each individual variable and their complex interactions for patients' outcome. These data might promote targeted strategies in enabling a more functional antitumor immune response.
Section snippets
Patients and tissue sampling
The archival samples were derived from 383 NSCLC patients with radical surgical resection in curative intent between 1992 and 2004 and diagnosed at the Institute for Pathology, Medical University of Innsbruck. Cases were selected only based on tissue preservation. Hematoxylin and eosin (H&E) stains from all available slides (complete tumor sample) were reclassified by 2 pathologists (W. S. and A. T.) without the knowledge of patient's data, according to the current World Health Organization
Histopathology and patient characteristics
In total, 383 cases were analyzed, with the following histologic subtypes: ACA, 193; SCC, 123; LCC, 54; adenosquamous carcinoma, 8; pleomorphic type, 4; and mucoepidermoid carcinoma, 1. Twenty were well, 161 moderately, and 202 poorly differentiated. Distribution of pathological tumor stage by Union Internationale Contre le Cancer (UICC) was as follows: stage I, 219; stage II, 67; stage IIIA, 59; stage IIIB, 20; and stage IV, 18. The patient population was composed of 280 men and 103 women
Discussion
This study was designed to analyze various immunologic parameters known to be critical for regulating adaptive and acquired mechanisms of adoptive tumor immune surveillance in a large cohort of patients with NSCLC. Among all variables evaluated in this study, TGF-β appeared to play the most important role. Expression of TGF-β in both tumor-infiltrating lymphocytes and in tumor cells was associated with significantly reduced postoperative survival time, especially for patients with SCC. Most
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