Investigating myeloid cells' role during cancer therapy is critical to developing novel strategies, as they shape the tumor microenvironment and modulate anti-tumor immune responses. Using single-cell RNA sequencing (scRNAseq), we examined the impact of the immunostimulant N-dihydrogalactochitosan (GC) on myeloid cells within MMTV-PyMT tumors. We discovered unique myeloid cell clusters with varied responses to GC, showing increased proportions of certain cell types, such as G-MDSC, monocytes, and DCs. Importantly, we observed significant upregulation of STING signaling-associated genes, indicative of conventional STING signaling and canonical NFkB signaling activation. Furthermore, our analysis showed an upregulation of proinflammatory cytokines in cDCs, and a significant reduction in M2-like macrophages post-GC treatment. This supports GC's potent immunostimulatory properties, activating key cells within the tumor microenvironment to enhance antitumor immunity.
A novel biopolymer, N-dihydrogalactochitosan (GC), is developed for inducing immune responses. GC stimulates innate and adaptive antitumor and antiviral immunities. In this study, we investigated the mechanism of GC-induced immune responses through in vitro and in vivo studies. We find that GC drives type I IFN production and IFN responses in antigen presenting cells (APCs). Furthermore, GC drives alternative activation of STING leading to inflammatory cell death that enhances dendritic cell (DC) activation. In vivo, GC induced a potent response of type I IFN and upregulated genes associated with STING signaling within the tumor microenvironment (TME). Because of its potent immunological stimulation ability and its unique mechanism in inducing the immune responses, GC has been used in combination with laser photothermal (PTT) for the treatment of cancers. We find that PTT+GC induced specific modulation of immune cells, positively corresponding to long-term survival of cancer patient.
γδT cell has gained importance during tumor immunotherapy. However, the transcriptional alterations remain unknown. Here, we applied a novel localized ablative immunotherapy (LAIT) to treat tumors in MMTV-PyMT mice and used single-cell RNA-sequencing to investigate the transcriptional profiles regulated by PTT, GC and LAIT (PTT+GC) in γδT cells. Subtypes of γδT cells included activated, cytotoxic, cycling cytotoxic, interferon enriched, antigen-presenting cell (APC)-like, and IL17-expressing γδT cells. Treatments specifically induced cell proportion in Il17-γδT cells while not other subtypes. LAIT-induced Il17-γδT gene expressions were positively associated with breast cancer patients’ survival, highlighting the clinical applications of Il17-γδT for cancer therapies.
Checkpoint inhibitor-based immunotherapy (CPI) has ushered in a new era in cancer treatment. CPI has shown promising outcomes in clinical studies, particularly in treating melanoma, non-small cell lung cancer, and a number of other cancers. However, CPI, currently using antibodies to CTLA-4, PD-1, and PD-L1, also has limitations. In most cases CPI can only be effective in a small percentage of patients of a given cancer. The major obstacles include initial resistance, refraction after initial response, high cost, and potential autoimmune side effects (particularly with high dose of checkpoint inhibitors). Biophotonics-based immunotherapy (BPI) uses a combination of phototherapy and immunostimulant, often through a local intervention. BPI has shown a great potential in inducing systemic, tumor-specific immunity against the target tumor. It has been used to treat metastatic cancers with promising outcomes. We anticipate that BPI can synergize with CPI by providing the quality and
The ideal strategy for treating metastatic cancers is a systemic, tumor-specific immunity induced by a local intervention. A local intervention-based immunotherapy was developed following this strategy: a local photothermal therapy (PTT), followed by an intratumoral administration of a potent immunostimulant, N-dihydrogalactochitosan (GC). This approach has shown great promise in preclinical and preliminary clinical studies. To understand the immunological mechanism of photo-immunotherapy, we used this local intervention-based immunotherapy to treat highly aggressive, metastatic breast tumors in a mouse model. We analyzed tumor-infiltrating immune cells. We observed a large number of infiltrating immune cells and increased immune activities in the treated tumors and secondary lymphoid organs (spleens). At the transcription level, we observed enriched both innate and adoptive immune cytokine signaling pathways in adaptive immune cells after the treatment of this local intervention
Immunotherapies hold high promise for the treatment of metastatic cancers. However, as a systemic approach, current immunotherapies have only achieved limited success in clinical studies. A local intervention-based immunotherapy has the potential to improve the therapeutic efficacy and to reduce systemic negative side effects of the immunotherapies. Specifically, the local treatment, together with appropriate immunological stimulation can change the tumor microenvironment to potentiate a tumor-specific immunity through the increased quantity and improved quality of tumor-infiltrating T cells. We used local, non-invasive laser irradiation of mammary tumors in a mouse model, followed by local administration of an immunostimulant. The treatment significantly delayed tumor growth and prolonged the animal survival. After the treatment, tumor-infiltrating immune cells were analyzed at the cellular and transcriptional levels. The specific responses of different subsets of immune cells
Laser Immunotherapy (LIT) is a novel treatment for metastatic cancer that uses laser irradiation and an immunostimulant to achieve lasting anti-tumor immunity. To increase photothermal conversion efficiency, LIT has used several types of agents tuned to absorb near-infrared (NIR) light. Polypyrrole (PPy) is an organic polymer with similar light absorbing characteristics to previously studied nanomaterials. We carried out dose-dependent PPy toxicity, stability, and photothermal experiments using a mouse breast cancer model. The marked stability under laser irradiation, coupled with PPy’s high photothermal conversion efficiency and low toxicity suggest that PPy could replace nanomaterials as a photothermal and drug-delivery agent.
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