TGF-beta and tumors--an ill-fated alliance

Abstract

Mechanisms of host defense can form an unwitting alliance with tumor cells to promote tumor progression, invasion, and dissemination to distant sites. By secreting TGF-beta, an immunoregulatory molecule designated for both promoting inflammation and dampening immune responses, the tumor tricks the host into supporting its expansion and survival. TGF-beta not only recruits leukocytes to secrete chemokines, growth factors, cytokines, and proteases in support of a tumor-friendly niche but also in a context-specific manner, incapacitates the emergent immune response. As a profound immunosuppressant, TGF-beta, both directly and through the generation of regulatory T cells, blunts immune surveillance, favoring tumor escape. Collectively, the ability of the tumor to hijack these host defense pathways can tip the balance in favor of the tumor.

Figure 1. Expression of TGFβ and TGFβ-related molecules in OSCC

A) In HNSCC, tumor cells and inflammatory cells in the stroma as well as in a necrotic region express high levels of TGFβ as detected by immunohistochemistry. B) Within regions of inflammatory cell infiltrates, identified by CD3⁺ T lymphocyte staining, are C) CD1a⁺ dendritic cells, D) CD68⁺ macrophages, E) IL-17⁺ lymphocytes, F) CD8⁺ T cells, G) Foxp3⁺ Treg, and H) intracellular phosphoSmad2 positive cells indicative of TGFβ signaling.

Figure 2. Putative immunoregulatory roles of TGFβ in tumor immunity

TGF-β secreted by tumor cells and infiltrating leukocytes and sequestered in the extracellular matrix, may represent an early communication between host cells and tumor cells. In its pro-inflammatory role, TGFβ exerts potent chemotactic effects on leukocytes (Recruitment) and participates in the differentiation of CD4⁺ T helper (Th) cell responses, including Th17 (RORγt ⁺) and Treg (Foxp3⁺) (T cell differentiation) activated by antigen presenting cell/dendritic cell (DC) presented tumor antigens (TA). Such pro-inflammatory events, intended to contribute to immune surveillance and to orchestrate an anti-tumor response, may be usurped by the tumor cells to provide growth factors, angiogenic factors (VEGF, etc.) and proteases(MMP1/2, plasmin, etc.) necessary to optimize tumor growth, invasion and metastasis. On the other hand, the immune suppressive effects of TGF-β assist the tumor in evasion of immune surveillance (Suppression). Unstimulated CD56⁺ NK cells and activated CD4⁺ and CD8⁺ T responder cells express TGFβR, which makes them vulnerable to secreted TGF-β and to suppression mediated through contact with Treg that express membrane TGF-β. Taking advantage of these pathways, the tumor often outmaneuvers the host defense system. While TGF-β represents but one of multiple contributing factors, its role is not insignificant in the growth and immune escape of the heterogeneous cellular constituents of a tumor. Like tissue repair, the evolution of tumors and host failure to eradicate them are regulated by complex interactions between malignant cells, epithelial cells, stromal cells, inflammatory cells, extracellular matrix, proteases, and a bevy of soluble mediators of communication.

Figure 3. IL-21 and IL-23 expression in HNSCC

Tissue sections from squamous cell carcinoma (A, B) and normal oral epithelium (C) were stained with antibodies for the cytokines IL-21 and IL-23. A) Inflammatory cell infiltrates that characterize squamous cell carcinoma contain cells consistent with lymphocytes that stain positively for IL-21. B) IL-23 staining included macrophage-like cell populations within the stromal cell regions. C) Little or no IL-23 and IL-21 stained inflammatory cells were identified within the relatively normal oral epithelium.