Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2018 Jul 24;10(8):242.
doi: 10.3390/cancers10080242.

The Tumor Microenvironment of Epithelial Ovarian Cancer and Its Influence on Response to Immunotherapy

Galaxia M Rodriguez  1   2 , Kristianne J C Galpin  3   4 , Curtis W McCloskey  5   6 , Barbara C Vanderhyden  7   8
Affiliations
Review

The Tumor Microenvironment of Epithelial Ovarian Cancer and Its Influence on Response to Immunotherapy

Galaxia M Rodriguez et al. Cancers (Basel). .

Abstract

Immunotherapy as a treatment for cancer is a growing field of endeavor but reports of success have been limited for epithelial ovarian cancer. Overcoming the challenges to developing more effective therapeutic approaches lies in a better understanding of the factors in cancer cells and the surrounding tumor microenvironment that limit response to immunotherapies. This article provides an overview of some ovarian cancer cell features such as tumor-associated antigens, ovarian cancer-derived exosomes, tumor mutational burden and overexpression of immunoinhibitory molecules. Moreover, we describe relevant cell types found in epithelial ovarian tumors including immune cells (T and B lymphocytes, Tregs, NK cells, TAMs, MDSCs) and other components found in the tumor microenvironment including fibroblasts and the adipocytes in the omentum. We focus on how those components may influence responses to standard treatments or immunotherapies.

Keywords: adipocytes; ascites; cancer-associated fibroblasts; epithelial ovarian cancer; exosomes; immunosuppression; prognostic factors; tumor infiltrating lymphocytes; tumor microenvironment; tumor-associated antigens.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Antitumoral responses in the EOC TME. Immunogenic cell death induces the release of DAMPs mediating the recruitment of innate cells and APCs. Lympho-attracting chemokines produced by APCs such as macrophages enable the recruitment of CD8+ T cells to the tumor niche. DCs are also attracted by the production of CCL5 derived from NK cells and CD4+ T cells. The pro-inflammatory milieu enables TAA sampling and presentation by APCs to T cells to induce their activation and expansion. Pro-inflammatory cytokines released by activated effector T cells, M1 macrophages and DCs allow the amplification of the antitumoral response, enabling the cytolytic death of EOC targeted by CD8+ TILs and NK cells. B cells also participate in antitumor immunity by presenting TAAs to CD8+ T cells, by facilitating Th1 polarization, T-cell expansion and by producing tumor specific antibodies. Danger-associated molecular patterns (DAMPs), Antigen presenting cells (APCs), tumor-associated antigens (TAAs), dendritic cells (DCs), natural killer cells (NKs), CD4+ T helper cell (Th1).
Figure 2
Figure 2
Tumor promoting network in the EOC TME. Outgrowth of EOC provokes hypoxia that induces the expression of chemokines to recruit MDSCs, Tregs, and TAMs. Tregs induce B7-H4 expression on APCs, subsequently blocking cytokine secretion, cytolytic activity, T-cell proliferation and promoting an immunosuppressive TME. EOC cells and MDSCs produce IDO that catabolizes tryptophan, rendering T cells anergic and dysfunctional. MDSCs and TAMs contribute to tumor growth, malignancy, metastasis and stemness. Several tumor promoting cytokines such as IL-6, IL-10 and TGFβ are prominent in the TME. VEGF released by EOC cells and CAFs stimulates angiogenic factors in the TME. CAFs also secrete many factors that mediate tumor cell migration, proliferation, invasion and chemoresistance, and contribute to the immunosuppressive TME. Adipocytes produce FA and cytokines that fuel tumor growth and omental metastasis. Myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs), regulatory T cells (Tregs), cancer-associated fibroblasts (CAFs), fatty acids (FA).
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Vesely M.D., Schreiber R.D. Cancer immunoediting: Antigens, mechanisms, and implications to cancer immunotherapy. Ann. N. Y. Acad. Sci. 2013;1284:1–5. doi: 10.1111/nyas.12105. - DOI - PMC - PubMed
    1. Santoiemma P.P., Powell D.J. Tumor infiltrating lymphocytes in ovarian cancer. Cancer Biol. Ther. 2015;16:807–820. doi: 10.1080/15384047.2015.1040960. - DOI - PMC - PubMed
    1. Santoiemma P.P., Reyes C., Wang L.-P., McLane M.W., Feldman M.D., Tanyi J.L., Powell D.J. Systematic evaluation of multiple immune markers reveals prognostic factors in ovarian cancer. Gynecol. Oncol. 2016;143:120–127. doi: 10.1016/j.ygyno.2016.07.105. - DOI - PubMed
    1. Stumpf M., Hasenburg A., Riener M.-O., Jütting U., Wang C., Shen Y., Orlowska-Volk M., Fisch P., Wang Z., Gitsch G., et al. Intraepithelial CD8-positive T lymphocytes predict survival for patients with serous stage III ovarian carcinomas: Relevance of clonal selection of T lymphocytes. Br. J. Cancer. 2009;101:1513–1521. doi: 10.1038/sj.bjc.6605274. - DOI - PMC - PubMed
    1. Zhang L., Conejo-Garcia J.R., Katsaros D., Gimotty P.A., Massobrio M., Regnani G., Makrigiannakis A., Gray H., Schlienger K., Liebman M.N., et al. Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N. Engl. J. Med. 2003;348:203–213. doi: 10.1056/NEJMoa020177. - DOI - PubMed