Interleukin-10 production by tumor infiltrating macrophages plays a role in Human Papillomavirus 16 tumor growth

Abstract Background Human Papillomavirus, HPV, is the main etiological factor for cervical cancer. Different studies show that in women infected with HPV there is a positive correlation between lesion grade and number of infiltrating macrophages, as well as with IL-10 higher expression. Using a HPV16 associated tumor model in mice, TC-1, our laboratory has demonstrated that tumor infiltrating macrophages are M2-like, induce T cell regulatory phenotype and play an important role in tumor growth. M2 macrophages secrete several cytokines, among them IL-10, which has been shown to play a role in T cell suppression by tumor macrophages in other tumor models. In this work, we sought to establish if IL-10 is part of the mechanism by which HPV tumor associated macrophages induce T cell regulatory phenotype, inhibiting anti-tumor activity and facilitating tumor growth. Results TC-1 tumor cells do not express or respond to IL-10, but recruit leukocytes which, within the tumor environment, produce this cytokine. Using IL-10 deficient mice or blocking IL-10 signaling with neutralizing antibodies, we observed a significant reduction in tumor growth, an increase in tumor infiltration by HPV16 E7 specific CD8 lymphocytes, including a population positive for Granzyme B and Perforin expression, and a decrease in the percentage of HPV specific regulatory T cells in the lymph nodes. Conclusions Our data shows that in the HPV16 TC-1 tumor mouse model, IL-10 produced by tumor macrophages induce regulatory phenotype on T cells, an immune escape mechanism that facilitates tumor growth. Our results point to a possible mechanism behind the epidemiologic data that correlates higher IL-10 expression with risk of cervical cancer development in HPV infected women.

This work was supported by Fundação de Amparo à Pesquisa do Estado de São Paulo, Brazil, processes 04/00749-2 and 09/03232-1. AB had a graduation fellowship from Fundação de Amparo à Pesquisa do Estado de São Paulo, process 05/59756-0. We thank Dr. Enrique Boccardo, Ludwig Institute for Cancer Research (São Paulo, Brazil) for the critical review of this manuscript. We would like to thank Dr. Philippe Guillaume and Dr. Immanuel Luescher (Ludwig Institute for Cancer Research, Lausanne, Switzerland) for providing the E7 and irrelevant MHC-I tetramers.

This work was supported by Fundação de Amparo à Pesquisa do Estado de São Paulo, Brazil, processes 04/007492 and 09/032321. AB had a graduation fellowship from Fundação de Amparo à Pesquisa do Estado de São Paulo, process 05/597560. We thank Dr. Enrique Boccardo, Ludwig Institute for Cancer Research (São Paulo, Brazil) for the critical review of this manuscript. We would like to thank Dr. Philippe Guillaume and Dr. Immanuel Luescher (Ludwig Institute for Cancer Research, Lausanne, Switzerland) for providing the E7 and irrelevant MHCI tetramers.