Characterizing tumor-promoting T cells in chemically induced cutaneous carcinogenesis

Abstract

There is a longstanding but poorly understood epidemiologic link between inflammation and cancer. Consistent with this, we previously showed that ␣␤ T cell deficiency can increase resistance to chemical carcinogenesis initiated by 7,12-dimethylbenz[a]anthracene and promoted by phorbol 12-myristate 13-acetate. This provoked the hypothesis that ␣␤ T cell deficiency removed T regulatory cells that limit the anti-tumor response or removed a specific tumor-promoting (T-pro) T cell population. Here we provide evidence for the latter, identifying a novel CD8 ؉ subset that is a candidate for T-pro cells. We demonstrate that CD8 cell-deficient mice show substantially less tumor incidence and progression to carcinoma, whereas susceptibility is restored by CD8 ؉ cell reconstitution. To characterize the putative T-pro cells, tumor-infiltrating lymphocytes were isolated from normal and CD4 ؊/؊ mice, revealing an activated population of T cell receptor ␣␤ ؉ CD8 ؉ CD44 ؉ CD62L ؊ cells expressing the inflammatory mediators IFN␥, TNF␣, and cyclooxygenase-2, but deficient in perforin, relative to recirculating cells of equivalent phenotype. This novel population of CD8 ؉ T cells has intriguing similarities with other lymphocytes that have been associated with tissue growth and invasiveness and has implications for inflammation-associated carcinogenesis, models of cancer immunosurveillance, and immunotherapeutic strategies.inflammation ͉ IFN␥ ͉ squamous cell carcinoma ͉ T cell receptor

Interferon‐γ down‐regulates NKG2D ligand expression and impairs the NKG2D‐mediated cytolysis of MHC class I‐deficient melanoma by natural killer cells

“…44 Interestingly, a T cell population with similar characteristics has also been detected in healthy human skin. 45 Thus, IFN-g might not always be supportive in terms of an effective tumor immune surveillance.…”

Tumor‐infiltrating IL‐17‐producing γδ T cells support the progression of tumor by promoting angiogenesis

“…Much attention has been paid to the finding that tumor stromal cells and tumor-associated macrophages, in part by producing IL-23, mainly contribute to the induction of cancer by promoting inflammation, whereas T cells suppress tumor development as part of the immunosurveillance system [23][24][25][26][27][28][29]. Recent research has provided evidence for the involvement of T cells in promoting tumor progression [28][29][30][31][32][33][34][35]; however, the precise effects of T cells and the cytokines they produce on tumorigenesis remain controversial.…”

“…Much attention has been paid to the finding that tumor stromal cells and tumor-associated macrophages, in part by producing IL-23, mainly contribute to the induction of cancer by promoting inflammation, whereas T cells suppress tumor development as part of the immunosurveillance system [23][24][25][26][27][28][29]. Recent research has provided evidence for the involvement of T cells in promoting tumor progression [28][29][30][31][32][33][34][35]; however, the precise effects of T cells and the cytokines they produce on tumorigenesis remain controversial.In this paper, we demonstrate that (i) IL-17 is a pro-tumor cytokine, which supports tumor growth by promoting angiogenesis; (ii) gd T cells, but neither TCRabCD4 1 T cells nor TCRabCD8 1 T cells, are the major cellular source of IL-17 in tumor-infiltrating lymphocytes (TIL); (iii) blood circulating gd T cells, but not skin-resident Vg5 1 gd T cells, infiltrate into the tumor site; (iv) tumor-infiltrating gd T cells differentiate into IL-17-producing cells but downmodulate their cytotoxic activity within the tumor microenvironment; (v) IL-17 produced by tumor-infiltrating gd T cells promotes tumor progression by inducing angiogenesis. Thus, this paper proposes the novel concept that IL-17-producing gd T cells play a crucial role as tumor-promoting T cells during tumor development.…”

“…40: 1927Immunol. -1937 Cellular immune responsewww.eji-journal.eu models [28][29][30][31][32][33][34][35]. However, the previous studies have not examined a pro-tumor function of gd T cells.…”

Targeting therapy-resistant cancer stem cells by hyperthermia

“…However, once a malignancy develops, immune cells, such as tumour-associated macrophages (TAMs), can also promote malignant cell growth by stimulating angiogenesis, invasion and metastasis [109], and high levels of TAMs are correlated with poor prognosis [110]. CD8þ and IFNÇ-producing helper T cells are also present frequently in the tumour microenvironment and they exert tumour and metastasis: promoting effects [111][112][113][114]. A recent study demonstrated that tumour-bearing mice had higher CSC-specific IgG levels in serum after vaccination with CSC lysate-activated dendritic cells (DCs).…”