HPV associated tumor cells control tumor microenvironment and leukocytosis in experimental models

Abstract

Human papillomavirus (HPV) is the main etiological factor for cervical cancer development. HPV is also associated with other anogenital and oropharyngeal tumors. HPV associated tumors are frequent and constitute a public health problem, mainly in developing countries. Therapy against such tumors is usually excisional, causing iatrogenic morbidity. Therefore, development of strategies for new therapies is desirable. The tumor microenvironment is essential for tumor growth, where inflammation is an important component, displaying a central role in tumor progression. Inflammation may be a causal agent, suppressor of anti-tumor T cell responses, or may have a role in angiogenesis, drug resistance, and metastasis. The aim of this work was to investigate the role of HPV transformed cells in the tumor microenvironment and tumor effects on myeloid populations in lymphoid organs in the host. We used experimental models, where we injected cervical cancer derived cell lines in immunodeficient mice, comparing HPV positive, SiHa, and HeLa cells (HPV 16 and HPV18, respectively), with HPV negative cell line, C33A. Our data shows that HPV positive cell lines were more efficient than the HPV negative cell line in leukocyte recruitment to the tumor microenvironment and increase in myeloid cell proliferation in the bone marrow and spleen. We also observed that HPV positive cells lines expressed significantly higher levels of IL-6 and IL-8, while C33A expressed significantly higher levels of IL-16 and IL-17. Finally, in spite of cytokine secretion by tumor cells, leukocytes infiltrating SiHa and HeLa tumors displayed almost negligible STAT3 and no NFκB phosphorylation. Only the inflammatory infiltrate of C33A tumors had NFκB and STAT3 activated isoforms. Our results indicate that, although from the same anatomical site, the uterine cervix, these cell lines display important differences regarding inflammation. These results are important for the design of immunotherapies against cervical cancer, and possibly against HPV associated tumors in other anatomical sites.

HPV16-associated tumors control myeloid cell homeostasis in lymphoid organs, generating a suppressor environment for T cells

“…(A) T cells isolated from C57BL/6 naive mice were transplanted through the tail vein into RAG1 Ϫ/Ϫ recipients, with or without TC-1 tumors. Interestingly, the in vivo cytokine-expression profile of the HPV-positive cell lines was similar among them but different from the prolife observed in the HPV-negative cell line [23]. A total of 2 ϫ 10 6 lymphocytes was injected in each recipient.…”

“…TC-1 tumors promote T reg expansion, possibly through an IL-10-dependent mechanism. We have shown previously that HPV-positive cervical cancer-derived cell lines induced leukocytosis in immunodeficient mice, whereas a HPV-negative cervical cancer-derived cell failed to do so [23]. TC-1 tumors in RAG1 Ϫ/Ϫ recipients displayed ϳ0.5-cm diameter at the moment of T cell transplant.…”

“…We have shown previously that TC-1 tumor-bearing mice exhibited a significant increase in myeloid populations in the spleen, as well as B lymphocytes in peripheral lymph nodes [21,22]. We have also shown, using cervical cancer-derived cell lines grafted in immunodeficient mice, that proliferation and accumulation of myeloid cells in lymphoid organs are HPV-mediated effects [23]. TC-1 tumors recruit M2-like macrophages (TAMs), which are capable of suppressing anti-tumor T cell responses.…”

Improving the efficiency of image guided brachytherapy in cervical cancer

“…Importantly, cervical brachytherapy offers direct access to the tumor and the possibility to obtain repeated tissue samples, and thus a high-resolution description of therapy response over time. This is a relatively underexploited facility but with new insights into the tumor microenvironment [56, 57, 58], particularly immune and inflammatory characteristics, and new therapeutic avenues such as immune checkpoint inhibition (e.g. PD-1 [59, 60, 61] and CTLA-4 [62, 63]), there is the opportunity to explore rational new drug-radiation combinations in partnership with technically optimized brachytherapy.…”

Bothrops jararaca and Bothrops erythromelas Snake Venoms Promote Cell Cycle Arrest and Induce Apoptosis via the Mitochondrial Depolarization of Cervical Cancer Cells

“…The method currently used in clinical medicine against different types of cancers, including cervical cancer, is surgical removal of the tumor followed by radiotherapy and chemotherapy [8]. Research on cancer is focused on discovery of new potential therapies, since the traditionally used drugs, such as Cisplatin (CDDP) and 5-Fluorouracil (5-FU), are often nonspecific and do not act directly on the tumor microenvironment.…”