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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
Journal article   Open access   Peer reviewed

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

Guoying Ni, Xiaodan Yang, Junjie Li, Xiaolian Wu, Ying Liu, Hejie Li, Shu Chen, Conor E Fogarty, Ian H Frazer, Guoqiang Chen, …
Clinical and Translational Immunology, Vol.10(8), pp.1-25
2021
DOI: https://doi.org/10.1002/cti2.1335
PMCID: PMC8369845
PMID: 34429969
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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 tumo7.36 MBDownloadView
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https://doi.org/10.1002/cti2.1335View
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Abstract

caerin peptide CD8+ T cell macrophage quantitative proteomics single‐cell RNA sequencing TC‐1 tumor tumor microenvironment
Objectives: Developing 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. Methods: We 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. Results: The 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. Conclusions: Caerin 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. In this study, we demonstrate that the intratumoral injection of caerin peptides significantly increases the survival time of vaccinated and anti‐PD‐1‐treated TC‐1 tumor‐bearing mice, through modulating the heterogenicity of tumor‐infiltrating macrophages. The combined treatments result in more activated tumor‐infiltrating T cells.

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