Intratumoral injection of caerin 1.1 and 1.9 peptides increases the efficacy of vaccinated TC‐1 tumor‐bearing mice with PD‐1 blockade by modulating macrophage heterogeneity and the activation of CD8+ T cells in the tumor microenvironment

• DOI: 10.1002/cti2.1335
• Publication Date: 2021-08-17T11:44:19Z
• Authors: Guoying Ni; Xiaodan Yang; Junjie Li; Xiaolian Wu; Ying Liu; Hejie Li; Shu Chen; Conor E Fogarty; Ian H Frazer; Guoqiang Chen; Xiaosong Liu; Tianfang Wang
• Keywords: quantitative proteomics; 0301 basic medicine; caerin peptide; 03 medical and health sciences; single‐cell RNA sequencing; Original Article; macrophage; TC‐1 tumor; Immunologic diseases. Allergy; RC581-607; CD8+ T cell; 3. Good health

AbstractObjectivesDeveloping a vaccine formula that alters the tumor‐infiltrating lymphocytes to be more immune active against a tumor is key to the improvement of clinical responses to immunotherapy. Here, we demonstrate that, in conjunction with E7 antigen‐specific immunotherapy, and IL‐10 and PD‐1 blockade, intratumoral administration of caerin 1.1/1.9 peptides improves TC‐1 tumor microenvironment (TME) to be more immune active than injection of a control peptide.MethodsWe compared the survival time of vaccinated TC‐1 tumor‐bearing mice with PD‐1 and IL‐10 blockade, in combination with a further injection of caerin 1.1/1.9 or control peptides. The tumor‐infiltrating haematopoietic cells were examined by flow cytometry. Single‐cell transcriptomics and proteomics were used to quantify changes in cellular activity across different cell types within the TME.ResultsThe injection of caerin 1.1/1.9 increased the efficacy of vaccinated TC‐1 tumor‐bearing mice with anti‐PD‐1 treatment and largely expanded the populations of macrophages and NK cells with higher immune activation level, while reducing immunosuppressive macrophages. More activated CD8+ T cells were induced with higher populations of memory and effector‐memory CD8+ T subsets. Computational integration of the proteome with the single‐cell transcriptome supported activation of Stat1‐modulated apoptosis and significant reduction in immune‐suppressive B‐cell function following caerin 1.1 and 1.9 treatment.ConclusionsCaerin 1.1/1.9‐containing treatment results in improved antitumor responses. Harnessing the novel candidate genes preferentially enriched in the immune active cell populations may allow further exploration of distinct macrophages, T cells and their functions in TC‐1 tumors.