No abstract

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.

Interleukin 10 (IL-10) belongs to IL-10 family cytokines that are critical for maintaining the integrity of epithelial tissues, protecting pathogenic infection, and preventing excessive immune responses to damage self. Temporal IL-10 signaling blockade enhances vaccine-induced tumor regression by CD8 + T cells. IL-10, especially pegylated IL-10, mediates tumor regression by expanding tumor-infiltrating CD8 + T cells. Moreover, targeting IL-10 enhances immune checkpoint inhibitor mediated tumor regression. In the current paper, we will review recent advances in this area and discuss the complexity of IL-10 manipulation for cancer therapy.

Multidrug resistance (MDR) has emerged as the main problem in anti-cancer therapy. Although MDR involves complex factors and processes, the main pivot is the expression of multidrug efflux pumps. P-glycoprotein (P-gp) belongs to the family of adenosine triphosphate (ATP)-binding cassette (ABC) transporters. It functions in cellular detoxification, pumping a wide range of xenobiotic compounds out of the cell. An attractive therapeutic strategy for overcoming MDR is to inhibit the transport function of P-gp and thus, increase intracellular concentration of drugs. Recently, various types of P-gp inhibitors have been found and used in experiments. However, none of them has passed clinical trials due to their high side-effects. Hence, the search for alternatives, such as plant-based P-gp inhibitors have gained attention recently. Therefore, we give an overview of the source, function, structure and mechanism of plant-based P-gp inhibitors and give more attention to cancer-related studies. These products could be the future potential drug candidates for further research as P-gp inhibitors.