Tissue Damage–Associated “Danger Signals” Influence T-cell Responses That Promote the Progression of Preneoplasia to Cancer

Abstract

T-cell responses may be shaped by sterile "danger signals" that are constituted by damage-associated molecular patterns (DAMP). However, whether and what type of adaptive immune responses are triggered in vivo by DAMPs induced by tumor progression are not well characterized. In this study, we report that the production of HMGB1, an established DAMP released by dying cells, was critical for tumor progression in an established mouse model of prostate cancer. HMGB1 was required for the activation and intratumoral accumulation of T cells that expressed cytokine lymphotoxina 1 b 2 (LT) on their surface. Intriguingly, these tumor-activated T cells recruited macrophages to the lesion and were essential to promote the preneoplasia to invasive carcinoma in an LTb receptor (LTbR)-dependent manner. Taken together, our findings suggest that the release of HMGB1 as an endogenous danger signal is important for priming an adaptive immune response that promotes malignant progression, with implications for cancer prevention and therapy. Cancer Res; 73(2); 629-39. Ó2012 AACR.

TLR4 is essential for dendritic cell activation and anti-tumor T-cell response enhancement by DAMPs released from chemically stressed cancer cells

“…It has been reported that DAMPs recognition can favor tumor progression by attracting immature myeloid cells and triggering the proliferation, migration and sprouting of endothelial cells in tumor beds. [6][7][8] Moreover, in CRC, HMGB1 expression is increased at metastatic sites compared with primary tumor sites in non-metastatic patients. 32 In addition to the putative role of HMGB1 in the promotion of tumor progression, certain preclinical and clinical data have revealed that HMGB1 seems to induce the functional maturation of DCs and to trigger protective anti-cancer T cell responses.…”

“…[3][4][5] However, DAMPs also play a putative role in the promotion of tumor progression by attracting immature myeloid cells and triggering tumor cell proliferation. [6][7][8] Thus, how to more efficiently trigger an anti-cancer immune response mediated by DAMPs is worthy of attention.…”

HMGB1 in health and disease

“…HMGB1 can be released, including by autocrine from the tumor cells and the surrounding cells under hypoxia or other environmental stimuli (Jube et al, 2012; Tafani et al, 2011; van Beijnum et al, 2013; Yan et al, 2012b). Extracellular HMGB1 mediates communication between cells in the tumor microenvironment by several receptors (e.g., RAGE and TLR4), which contributes to tumor growth and spreads by several mechanisms including sustenance of the inflammatory microenvironment (Bald et al, 2014; Gebhardt et al, 2008; Mittal et al, 2010), fulfillment of metabolic requirements (Kang et al, 2013a; Tang et al, 2011b), promotion of invasion and metastasis (Huttunen et al, 2002; Kuniyasu et al, 2002; Sasahira et al, 2005a; Taguchi et al, 2000), inhibition of antitumor immunity (He et al, 2012c; Kusume et al, 2009; Liu et al, 2011f), and promotion of angiogenesis (Sasahira et al, 2007; van Beijnum et al, 2012). Thus, inhibition of HMGB1 release and activity can block tumor growth and development.…”

Danger signalling during cancer cell death: origins, plasticity and regulation

“…46 Similarly, in a transgenic mouse model of prostate cancer, the release of HMGB1 was associated with priming of adaptive immunoregulatory response that facilitated malignant progression. 90 Gemcitabine and 5-fluorouracil were shown to activate the proapoptotic protein BAX in myeloid-derived suppressor cells (MDSC), inducing lysosomal destabilization and release of cathepsin B. 91 The latter triggers NLRP3 inflammasomes resulting in the secretion of proinflammatory cytokines (including IL-1b) that may curtail anti-tumour immunity by promoting IL-17 secretion from CD4 þ T cells.…”