Modulation of T cell metabolism to restore immune cell effector functions against high-grade serous ovarian cancer
Final Report Abstract
A malignant tumor is not only composed of cancer cells but also harbors non-mutated cells, such as immune cells, fibroblasts, adipocytes, and endothelial cells. These cells can significantly influence the tumor's development, its growth, and metastasis. Immune cells like CD8+ T cells, can inhibit cancer growth. On the other hand, fibroblasts can secrete growth factors and extracellular matrix that support cancer growth and metastasis. These fibroblasts are known as cancer-associated fibroblasts (CAFs). Despite the well-established tumor-supporting role of these CAFs, there is still no clinically approved CAF-specific cancer therapy. To better understand the role of CAFs and to develop potential therapies, we investigated how CAFs change their gene expression during tumor development. For this purpose, we conducted immunofluorescence-based spatial transcriptomics and compared the gene expression of CAFs in the stroma of ovarian carcinoma with nonmalignant stroma adjacent to the tumor. Interestingly, we found that N-methyltransferase (NNMT) is significantly overexpressed in CAFs. A literature review subsequently revealed that high stromal NNMT expression is associated with poor prognosis for patients with ovarian, lung, and colon carcinomas. However, the exact mechanism by which NNMT expression in CAFs worsens the prognosis of patients is not yet known. Gene Set Enrichment Analysis (GSEA) as well as analyses of the proteome of normal fibroblasts and fibroblasts overexpressing NNMT have shown that NNMT overexpression leads to increased secretion of complement factors in fibroblasts. These complement factors, in turn, activate the complement cascade, leading to the recruitment of myeloid cells that inhibit CD8+ T cells. These immuno-suppressive myeloid cells suppress the immune response against the cancer, allowing the cancer to grow and metastasize. To prevent this, we developed a drug that inhibits NNMT in CAFs, thus preventing the activation of the complement system. This drug significantly inhibited tumor growth and metastasis in murine cancer models. In summary, our research highlights NNMT as a promising therapeutic target for CAFs. Inhibiting NNMT can reduce the infiltration of immune-suppressive myeloid cells and therefore alleviate the inhibition of CD8+ T cells.
Publications
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Neoadjuvant Chemotherapy Induces Genomic and Transcriptomic Changes in Ovarian Cancer. Cancer Research, 82(1), 169-176.
Javellana, Melissa; Eckert, Mark A.; Heide, Janna; Zawieracz, Katarzyna; Weigert, Melanie; Ashley, Sarah; Stock, Elizabeth; Chapel, David; Huang, Lei; Yamada, S. Diane; Ahmed, Ahmed Ashour; Lastra, Ricardo R.; Chen, Mengjie & Lengyel, Ernst
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Abstract 4462: Immunoregulatory effects of NNMT-expressing cancer-associated fibroblasts. Cancer Research, 83(7_Supplement), 4462-4462.
Heide, Janna; Piffko, Andras; Bilecz, Agnes J.; Teich, Ethan A.; Schweizer, Lisa; Alhunayan, Sayed R.; Yang, Kaiting & Lengyel, Ernst
