Targeting immune and desmoplastic tumor microenvironment to sensitize gynecological cancer cells to therapy

Cancer is a pervasive global threat that manifests with diverse clinical attributes and notable mortality rates, particularly attributable to its metastatic potential in solid cancers. These tumours encompass various types including epithelial cancers like high-grade serous ovarian cancer (HGSC) and mesenchymal cancers like uterine sarcomas (USs).

Despite the differing origins of USs and HGSCs, the pivotal concept of the transition between epithelial and mesenchymal states remains remarkably plastic, occurring frequently in these cancers. This plasticity holds immense significance in understanding tumour invasiveness and metastasis. The TME emerges as a crucial influencer as exerting its impact on cancer progression, epithelial-mesenchymal transition (EMT), metastasis, and even chemoresistance. The TME comprises various elements, with the extracellular matrix (ECM) containing structural proteins like collagens, standing out as a key constituent.

Moreover, immune cells within the TME, such as lymphocytes and macrophages, actively engage in interactions with both the ECM and cancer cells shaping local responses to kill the cancer cells or support their growth. Understanding the intricate tumour-TME interactions become imperative in formulating effective strategies aimed at modulating the immune response and halting cancer progression. Therefore, a nuanced comprehension of these complexities is crucial in developing strategies to combat cancer effectively. This thesis focuses on identifying TME factors, including ECM components and immune cell interactions in gynaecological cancers for improved precision medicine including immunotherapies and other novel treatments.

In Paper I, Uterine sarcomas present distinct immune signatures with prognostic value, independent of tumour type. FOXP3+ cell density and CD8+/FOXP3+ ratio (CFR) correlated with favourable survival in endometrial stromal sarcomas (ESS) and undifferentiated uterine sarcomas (USS). The CFR also highlighted the correlation between CFR high and upregulation of ECM organization pathways. In Paper II conversely, uterine leiomyosarcomas (uLMS) showed distinct behaviours, with lower collagen density and upregulated ECM remodelling enzymes correlating with aggressiveness. MMP-14 and yes-associated protein 1 (YAP) were required for uLMS growth and invasion. In Paper Ⅲ, shifting to HGSC, matrisome, a group of proteins encoded by genes for core ECM proteins 4 (collagens, proteoglycans, and ECM glycoproteins) and ECM-associated proteins (proteins structurally resembling ECM proteins, ECM remodelling enzymes, and secreted factors) in the ECM, showed changes in expression depending on the type of tumour host tissues and after chemotherapy. Collagen VI, among scrutinized proteins, exhibited elevated expression linked to shortened survival in ovarian cancer patients. Mechanistically, collagen VI promoted platinum resistance via the stiffness-dependent β1 integrin-pMLC and YAP/TAZ pathways in HGSC cell lines

In summary, this integrated exploration of uterine sarcomas and ovarian cancer provides a comprehensive understating of their TME. The study elucidates diverse immune and molecular features, offering potential prognostic markers and therapeutic targets. The findings underscore the complexity of these gynaecological malignancies, emphasizing the need for tailored approaches in understanding and combating these diseases.

List of scientific papers

I. Gultekin O*, Gonzalez-Molina J*, Hardell E, Moyano-Galceran L, Mitsios N, Mulder J, Kokaraki G, Isaksson A, Sarhan D, Lehti K*, Carlson JW*. FOXP3+ T cells in uterine sarcomas are associated with favourable prognosis, low extracellular matrix expression and reduced YAP activation. NPJ Precis Oncol. 2021 Nov;5(1):97. *Equal contribution.
https://doi.org/10.1038/s41698-021-00236-6

II. Gonzalez-Molina J, Hahn P, Falcão RM, Gultekin O, Kokaraki G, Zanfagnin V, Braz Petta T, Lehti K, Carlson JW. MMP14 expression and collagen remodelling support uterine leiomyosarcoma aggressiveness. Mol Oncol. 2023 Apr.
https://doi.org/10.1002/1878-0261.13440

III. Pietilä EA, Gonzalez-Molina J, Moyano-Galceran L, Jamalzadeh S, Zhang K, Lehtinen L, Turunen SP, Martins TA, Gultekin O, Lamminen T, Kaipio K, Joneborg U, Hynninen J, Hietanen S, Grénman S, Lehtonen R, Hautaniemi S, Carpén O, Carlson JW, Lehti K. Co-evolution of matrisome and adaptive adhesion dynamics drives ovarian cancer chemoresistance. Nat Commun. 2021 06;12(1):3904.
https://doi.org/10.1038/s41467-021-24009-8