Caerin 1.1/1.9 Enhances Antitumour Immunity by Activating the IFN-α Response Signalling Pathway of Tumour Macrophages

SIMPLE SUMMARY: Cancer immunotherapy has been enabled by immune checkpoint blockade, but is ineffective in many patients, mainly due to the high complexity of the immune-suppressive tumour microenvironment (TME). Here, with a murine transplantable tumour model, we demonstrate that host-defence caerin 1.1/1.9 peptides can alter the macrophages in the TME from immunosuppressive to immune active phenotypes, which appeared consistent with the macrophages observed at early-stage cervical cancer patients. The modulated macrophages by caerin 1.1/1.9 show significant activation of Type I interferons response and Stat1 signalling, rendering animals resistant to further tumour challenges. Our results indicate that caerin 1.1 and 1.9 treatment may enhance the efficacy of current immunotherapy modalities. ABSTRACT: Macrophages are one of the essential components of the tumour microenvironment (TME) of many cancers and show complex heterogeneity and functions. More recent research has been focusing on the characterisation of tumour-associated macrophages (TAMs). Previously, our study demonstrated that caerin 1.1/1.9 peptides significantly improve the therapeutic efficacy of combined specific immunotherapy and immune checkpoint blockade in a murine transplantable tumour model (TC-1). In this study, the mice inoculated with TC-1 tumour were immunised differently. The TAMs were isolated using flow cytometry and characterised by cytokine ELISA. The survival rates of mice with different treatments containing caerin 1.1/19 were assessed comparatively, including those with/without macrophage depletion. The single-cell RNA sequencing (scRNA-seq) data of previous studies were integrated to further reveal the functions of TAMs with the treatments containing caerin 1.1/1.9. As a comparison, the TAMs of stage I and II cervical cancer patients were analysed using scRNA-seq analysis. We demonstrate that caerin induced tumour clearance is associated with infiltration of tumours by IL-12 secreting Ly6C+F4/80+ macrophages exhibiting enhanced IFN-α response signalling, renders animals resistant to further tumour challenge, which is lost after macrophage depletion. Our results indicate that caerin 1.1/1.9 treatment has great potential in improving current immunotherapy efficacy.