Tumour microenvironment in serous ovarian cancer

Ovarian cancer is the seventh most common malignancy in women worldwide and the most lethal gynaecological malignancy in developed countries. The epithelial subtype is divided in five main histologic groups, of which the high-grade serous is the most common subtype. Advanced stage at diagnosis, poor prognosis and high incidence of resistance to therapy constitute the most important challenges for patients with ovarian cancer. The search to identify new prognostic and predictive markers represents one of the major goals in the research field of high-grade serous ovarian cancer (HGSOC).

During tumour development and progression, the ovarian stroma, constituted by blood vessels, fibroblasts, smooth muscle cells and connective tissue, sustains cancer cells through synergistic paracrine communications. This thesis aimed at studying the components of tumour microenvironment in serous ovarian cancer, especially HGSOC, and their possible association with survival and response to therapy.

We identified PDGFRβ positive stroma fibroblasts and perivascular cells as a determinant of poor survival in serous ovarian cancer. When we characterized PDGFRβ positive stroma and vasculature of ovarian cancer, compared to renal and colorectal cancer, we found both similarities and differences. We also studied the interaction between cancer-associated fibroblasts and immune cells and noted an inhibitory effect of FAP positive fibroblasts in patients with high tumour infiltration of CD8 positive T cells on response to platinum-based treatment in a population of HGSOC patients. On the same population, we studied the macrophage profile and discovered a correlation of two distinct subtypes of macrophages (CD11c and CD80 positive) in specific tumour localizations, with overall and progression-free survival respectively, indicating independent effects of these subsets on natural course of the disease and response to treatment.

In summary, our research identified a number of tumour stroma-related measurable features associated with survival and response to treatment. Our findings support continued analyses of ovarian cancer tumour microenvironment in order to discover and develop new prognostic and predictive tools, to improve the clinical outcome in ovarian cancer.

List of scientific papers

I. Corvigno S., Wisman G.B.A., Mezheyeuski A., Van der Zee A.G.J., Nijman H.W., Åvall-Lundqvist E., Östman A., Dahlstrand H. (2016). Markers of fibroblasts-rich tumor stroma and perivascular cells in serous ovarian cancer: inter- and Intra-patient heterogeneity and impact on survival. Oncotarget. 7(14), 18573-18584.
https://doi.org/10.18632/oncotarget.7613

II. Frodin M., Mezheyeuski A., Corvigno S., Harmenberg U., Sandström P., Egevad L., Johansson M., Östman A. (2017). Perivascular PDGFR-β is an independent marker for prognosis in renal cell carcinoma. British Journal of Cancer. 116, 195-201.
https://doi.org/10.1038/bjc.2016.407

III. Corvigno S., Frodin M., Wisman G.B.A., Nijman H.W., Van der Zee A.G.J., Jirström K., Nodin B., Johansson M., Dahlstrand H., Mezheyeuski A., Östman A. (2017). Multi-parametric profiling of renal cell, colorectal and ovarian cancer identifies tumor-type-specific stroma phenotypes and a novel vascular biomarker. [Submitted]

IV. Corvigno S., Mezheyeuski A., Carlson J.W., Fernebro J., Klein C., Åvall Lundqvist E., Östman A., Dahlstrand H. (2017). FAP+ cancer-associated fibroblasts affect platinum-response in a subset of high-grade serous ovarian cancer with high T-cell infiltration. [Manuscript]

V. Corvigno S., Mezheyeuski A., Carlson J.W., Fernebro J., Åvall-Lundqvist E., Rolny C., Östman A*., Dahlstrand H*. (2017) Marker- and localization-defined subsets of CD68-positive cells show specific associations with prognosis and response to treatment in highgrade serous ovarian cancer. [Manuscript]