Interactions of myeloid cells with tumor microenvironment as a therapeutic target in head and neck cancer

Immune evasion of cancer is induced by interaction between immune cells with tumor microenvironment (TME). CCL2 is a major chemoattractant for myeloid cells in TME and is associated with immunosuppression at the tumor site and poor prognosis. Aiming to prevent interaction of myeloid cells with immunosuppressive TME, we developed a peptide fragment of CCL2, MMIb, which blocks glycosaminoglycan-CCL2 interaction and thus disturbs the guiding chemokine gradient for myeloid cells. In translational approach, the effect of MMIb was evaluated in vitro and in vivo in murine model of oropharyngeal carcinoma, and verified in human in vitro system using head and neck cancer (HNC) explants. Molecular mechanism was investigated using LC-MS/MS and confirmed by multiparameter flow cytometry. Treatment with MMIb prevented infiltration of tumors with myeloid cells and suppressed tumor growth in vivo. Analysis of tumor proteome after MMIb treatment revealed upregulation of the pathways responsible for antigen uptake, processing and presentation via MHCI and MHCII, immunostimulation (PDL1^-, TGFb^-, IL12⁺) and lymphocyte activation (PD1^-, Fas⁺, GrzmB⁺). Moreover, MMIb prevented tumor-induced immunosuppression in tumor-draining lymph nodes. In human system, MMIb suppressed migration of labeled monocytes into the HNC explants and their immunosuppressive polarization. Altogether, we can demonstrate the efficiency of MMIb to therapeutically prevent immune cell/TME interactions and therefore to maintain their anti-tumor potential. Importantly, the effect is not limited to one molecule or one cell type, but covers the broad range of immunoregulatory mediators, making it less sensitive to immune evasion. We believe that this compound can be considered as immunosupportive medication in cancer.

Publication History

Article published online:
19 April 2024