Molecular Landscape of the Coagulome of Oral Squamous Cell Carcinoma

Abstract

Background: Hemostatic complications, ranging from thromboembolism to bleeding, are a significant source of morbidity and mortality in cancer patients. The tumor coagulome represents the multiple genes and proteins that locally contribute to the equilibrium between coagulation and fibrinolysis. We aimed to study the coagulome of Oral Squamous Cell Carcinoma (OSCC) and examine its link to the tumor microenvironment (TME). Methods: We used data from bulk tumor DNA/RNA-seq (The Cancer Genome Atlas), single-cell RNA-seq data and OSCC cells in culture. Results: Among all tumor types, OSCC was identified as the tumor with the highest mRNA expression levels of F3 (Tissue Factor, TF) and PLAU (urokinase type-plasminogen activator, uPA). Great inter- and intra-tumor heterogeneity were observed. Single-cell analyses showed the coexistence of subpopulations of pro-coagulant and pro-fibrinolytic cancer cells within individual tumors. Interestingly, OSCC with high F3 expressed higher levels of the key immune checkpoint molecules CD274/PD-L1, PDCD1LG2/PD-L2 and CD80, especially in tumor dendritic cells. In vitro studies confirmed the particularity of the OSCC coagulome and suggested that thrombin exerts indirect effects on OSCC cells. Conclusions: OSCC presents a specific coagulome. Further studies examining a possible negative modulation of the tumor’s adaptive immune response by the coagulation process are warranted.

Targeting coagulation to unlock antitumor immunity?

“…Of all primary tumors, Oral Squamous Cell Carcinoma (OSCC), the most frequent tumors of the oral cavity, have the highest expression of F3 , the gene encoding Tissue Factor (TF), a key initiator of the coagulation cascade. 8 , 9 The role of coagulation should therefore be reconsidered for each tumor, outside of the pre-conceived ideas generated by the study of systemic vascular complications of cancer. 9 Myeloid cells that infiltrate the tumors could be both a source and a target of coagulation factors.…”

“… 8 , 9 The role of coagulation should therefore be reconsidered for each tumor, outside of the pre-conceived ideas generated by the study of systemic vascular complications of cancer. 9 Myeloid cells that infiltrate the tumors could be both a source and a target of coagulation factors. Indeed, monocytic cells contribute greatly to the expression of the fibrinolysis genes, since these cells express high mRNA levels of PLAU (encoding the urokinase type-plasminogen activator, uPA) and SERPINE1 (encoding PAI-1).…”

“…Indeed, monocytic cells contribute greatly to the expression of the fibrinolysis genes, since these cells express high mRNA levels of PLAU (encoding the urokinase type-plasminogen activator, uPA) and SERPINE1 (encoding PAI-1). 8 , 9 Importantly, the coagulation cascade does not simply correlate with the tumor recruitment of immune cells. 8 , 9 In OSCC for example, there is no clear link between tumor infiltration by the major families of immune cells and the expression of F3 .…”

“… 8 , 9 Importantly, the coagulation cascade does not simply correlate with the tumor recruitment of immune cells. 8 , 9 In OSCC for example, there is no clear link between tumor infiltration by the major families of immune cells and the expression of F3 . 9 Single-cell analyses however point to the existence of an activated TAM phenotype, characterized by high expression of the cytokine CXCL2 (C-X-C Motif Chemokine Ligand 2) in tumors that express high levels of F3 .…”

“… 8 , 9 In OSCC for example, there is no clear link between tumor infiltration by the major families of immune cells and the expression of F3 . 9 Single-cell analyses however point to the existence of an activated TAM phenotype, characterized by high expression of the cytokine CXCL2 (C-X-C Motif Chemokine Ligand 2) in tumors that express high levels of F3 . In this subset of tumors, dendritic cells, key players in antitumor adaptive immunity, also express high levels of the immune checkpoint molecule CD274 /PD-L1.…”