RESUMEN
Evidence links chronic inflammation with cancer, but cellular mechanisms involved in this process remain unclear. We have demonstrated that in humans, inflammatory conditions that predispose to development of skin and colon tumors are associated with accumulation in tissues of CD33+S100A9+ cells, the phenotype typical for myeloid-derived suppressor cells in cancer or immature myeloid cells (IMCs) in tumor-free hosts. To identify the direct role of these cells in tumor development, we used S100A9 transgenic mice to create the conditions for topical accumulation of these cells in the skin in the absence of infection or tissue damage. These mice demonstrated accumulation of granulocytic IMCs in the skin upon topical application of 12-O-tetradecanoylphorbol-13-acetate (TPA), resulting in a dramatic increase in the formation of papillomas during epidermal carcinogenesis. The effect of IMCs on tumorigenesis was not associated with immune suppression, but with CCL4 (chemokine [C-C motif] ligand 4)-mediated recruitment of IL-17-producing CD4+ T cells. This chemokine was released by activated IMCs. Elimination of CD4+ T cells or blockade of CCL4 or IL-17 abrogated the increase in tumor formation caused by myeloid cells. Thus, this study implicates accumulation of IMCs as an initial step in facilitation of tumor formation, followed by the recruitment of CD4+ T cells.
Asunto(s)
Linfocitos T CD4-Positivos/metabolismo , Células Mieloides/patología , Neoplasias Cutáneas/patología , Animales , Linfocitos T CD4-Positivos/inmunología , Calgranulina B/metabolismo , Transformación Celular Neoplásica/patología , Quimiocina CCL4/metabolismo , Colitis/metabolismo , Colitis/patología , Femenino , Humanos , Ratones Transgénicos , Células Mieloides/efectos de los fármacos , Células Mieloides/metabolismo , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/metabolismo , Acetato de Tetradecanoilforbol/análogos & derivados , Acetato de Tetradecanoilforbol/toxicidadRESUMEN
Myeloid-derived suppressor cells (MDSC) are widely implicated in immune suppression associated with tumor progression and chronic inflammation. However, very little is known about their possible role in tumor development. Here, we evaluated the role of MDSC in two experimental models of lung cancer: inflammation-associated lung cancer caused by chemical carcinogen urethane in combination with exposure to cigarette smoke; and a transgenic CC10Tg model not associated with inflammation. Exposure of mice to cigarette smoke alone resulted in significant accumulation in various organs of cells with typical MDSC phenotype (Gr-1(+)CD11b(+)). However, these cells lacked immunosuppressive activity and could not be defined as MDSC. When cigarette smoke was combined with a single dose of urethane, it led to the development of tumor lesions in lungs within 4 months. By that time, Gr-1(+)CD11b(+) cells accumulated in the spleen and lung and had potent immunosuppressive activity, and thus could be defined as MDSC. In the CC10Tg model, accumulation of immunosuppressive MDSC was observed only at 4 months of age, after the appearance of tumor lesions in the lungs. Accumulation of MDSC in both models was abrogated in S100A9 knockout mice. This resulted in a dramatic improvement in survival of mice in both models. Thus, cigarette smoke results in the expansion of immature myeloid cells lacking suppressive activity. Accumulation of bona fide MDSC in both models was observed only after the development of tumor lesions. However, MDSC played a major role in tumor progression and survival, which suggests that their targeting may provide clinical benefits in lung cancer.