Immune Enhancement of Skin Carcinogenesis by CD4+ T Cells

Abstract

In a transgenic model of multi-stage squamous carcinogenesis induced by human papillomavirus (HPV) oncogenes, infiltrating CD4+ T cells can be detected in both premalignant and malignant lesions. The lymph nodes that drain sites of epidermal neoplasia contain activated CD4+ T cells predominantly reactive toward Staphylococcal bacterial antigens. HPV16 mice deficient in CD4+ T cells were found to have delayed neoplastic progression and a lower incidence of tumors. This delay in carcinogenesis is marked by decreased infiltration of neutrophils, and reduced activity of matrix metalloproteinase-9, an important cofactor for tumor progression in this model. The data reveal an unexpected capability of CD4 T cells, whereby, proinflammatory CD4+ T cells, apparently responding to bacterial infection of dysplastic skin lesions, can inadvertently enhance neoplastic progression to invasive cancer.

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.…”

Infiltrating neutrophils mediate the initial angiogenic switch in a mouse model of multistage carcinogenesis

“…In regard to the innate immune system, despite its capability to stimulate acquired immune responses, the weight of the evidence indicates that infiltration by innate immune cell types is tumorpromoting in many organs and tumorigenesis pathways (1,7,8). In addition to protumorigenic activities of tumor associated macrophages (9-11), neutrophils also have been shown to enhance the in vitro invasive and in vivo metastatic potential of syngeneic tumor cells by facilitating invasion into basement membrane (7).Genetically engineered mouse models of cancer are proving instructive about the immunobiology of tumors, revealing both enhancing and antagonizing roles played by the adaptive and innate immune system (4,5,(12)(13)(14). RIP1-Tag2 transgenic mice constitute a well characterized prototypical model for multistep carcinogenesis, involving the pancreatic islets, which has provided insights into immune interactions during tumorigenesis.…”

“…Genetically engineered mouse models of cancer are proving instructive about the immunobiology of tumors, revealing both enhancing and antagonizing roles played by the adaptive and innate immune system (4,5,(12)(13)(14). RIP1-Tag2 transgenic mice constitute a well characterized prototypical model for multistep carcinogenesis, involving the pancreatic islets, which has provided insights into immune interactions during tumorigenesis.…”