Protumoral Role of Complement Activation in Murine Sarcoma and Skin Cancer Models

Di Marco, Sabrina (2020). Protumoral Role of Complement Activation in Murine Sarcoma and Skin Cancer Models. PhD thesis The Open University.



Cancer related inflammation (CRI) plays a fundamental role in fueling tumor appearance and development. Despite the important contribution of complement activation to inflammation establishment, its role in CRI still remains understudied. Recently, our group demonstrated the pro-malignant role of complement activation in models of mesenchymal [3-methycolanthrene (3-MCA)-induced] and epithelial [dimethylbenz-α-anthracene/terephthalic acid (DMBA/TPA)-induced)] carcinogenesis, showing that mice deficient for the central complement component C3 were protected from tumor development. The aims of this thesis were the investigation on the role of complement activation in the context of cancer-related inflammation in mouse model of sarcoma and skin carcinogenesis.

The experiments revealed the deposition of C3-cleavage products on vessels and tumor cells. C3 deposition on cancer cells was also observed in 3-MCA-derived and MN/MCA1 sarcoma cells in vitro, and it was affected by alterations in the glycocalyx composition. C3-/-, MBL1/2-/- and C4-/- mice showed reduced susceptibility to 3-MCA-induced carcinogenesis, whereas C1q deficiency had marginal effects only in the transplanted MN/MCA1 sarcoma model, suggesting that the lectin pathway was mainly responsible for complement activation. The deficiency of Complement 3a receptor (C3aR), but not of C5aR1 and C5aR2, mirrored the phenotype of C3-/- mice, suggesting that C3a/C3aR signaling was the C3 downstream mechanism supporting sarcoma development. Further, C3 and C3aR deficiency were associated with reduced accumulation and functional skewing of tumor-associated macrophages, increased T cell activation and response to anti-PD-1 therapy. Transcriptional profile analysis revealed that C3 deficiency was associated with the upregulation of several genes involved in the MHC II-dependent antigen presentation process in macrophages. In contrast, in the DMBA/TPA model, the C5a/C5aR1 signaling was responsible for skin lesion development. Finally, in human undifferentiated pleomorphic sarcoma (UPS) the lack of C3aR expression was associated with higher recurrence-free and metastasis-free survival, suggesting that C3a/C3aR signaling was responsible for sarcoma aggressiveness and progression in humans as well as in mouse models.

Our results indicate that complement activation occurs in tumor, although the effector mechanism/s involved are context-dependent.

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