Tumor vaccine inducing effective and perdurable antitumor immunity has a great potential for cancer prevention and therapy. The key indicator for a successful tumor vaccine is to boost the immune system to produce more memory T cells. Although many tumor vaccines have been designed in the past two decades, few of them involve actively regulating immune memory CD8+T cells. The behavior of tumor-associated antigens (TAA) in stimulating the immune system is related to the formation of immune memory. At the same time, the metabolic pattern of memory CD8+T cells changed significantly compared to effector T cells. Here we present a tumor vaccine vector (TA-Met@MS) by encapsulating tumor antigen (TA, the whole tumor cell antigen induced with photothermal-therapy (PTT) as a TAA model), metformin (Met, an activator of AMP-activated protein kinase (AMPK)) and Hollow gold nanospheres (HAuNS, with photothermal conversion effect in the near infrared (NIR) region) into poly (lactic-co-glycolic acid) (PLGA) microspheres. TA via the treatment with PTT showed high immunogenicity and immune-adjuvant effectiveness. We found that NIR light-mediated photothermal effect lead to a pulsed-release behavior of TA and Met from the microspheres, based on their sustained release. The released TA regulated primary T cell expansion and contraction, and stimulated the production of effector T cells at the early immunization stage. The metabolic behavior of the cells was then intervened from glycolysis into fatty acids oxidation (FAO) through the activation of AMPK mediated by the released Met, which enhanced cell survival and facilitated the differentiation of memory CD8+T cells. Our study may present a valuable insight to design tumor vaccine for enhanced cancer prevention and therapy.
Abstract Vaccination is a widely‐accepted resort against the invasion or proliferation of bacteria, parasites, viruses, and even cancer, which accounts heavily on an active involvement of CD8 + T cells. As one of the pivotal strategies taken by dendritic cells (DCs) to promote the responsiveness of CD8 + T cells to exogenous antigens, cross presentation culminates in an elevated overall host defense against cancer or infection. However, the precise mechanisms regulating such a process remains elusive, and current attempts to fuel cross presentation usually fail to exert efficiency. Here, model antigen OVA‐loaded, endoplasmic reticulum (ER)‐targeting cationic liposome (OVA@lipoT) is developed and characterized with a booster effect on the activation and maturation of DCs. Moreover, OVA@lipoT pulsed DCs exhibit overwhelming superiority in triggering cytotoxic T lymphocyte response both in vivo and in vitro. Data reveal that lipoT alters the intracellular trafficking and presenting pathway of antigen, which promotes cross presentation and bears close relationship to the ER‐associated degradation (ERAD). These results may drop a hint about the interconnectivity between cross presentation and ER‐targeted antigen delivery, provide extra information to the understanding of ERAD‐mediated cross priming, and even shed new light on the design and optimization of vaccines against currently intractable cancers or virus‐infection.
M2-tumor associated macrophages (TAMs) play an important role in tumor genesis, progression, and metastasis, and repolarizing M2-TAMs to immune-promoting M1 type is increasingly recognized as a promising strategy against the clinically intractable carcinomas. It is observed that M2 macrophages have a high tropism to the tumor hypoxic area, with their endoplasmic reticulum (ER) stress-associated IRE1-XBP1 pathway activated to inhibit cell glycolysis, promote oxidative phosphorylation (OXPHOS), and facilitate intracellular lipid accumulation, which in turn shapes the typical phenotypes of M2-TAMs, suggesting that manipulating the ER stress response of M2-TAMs might stand as a breakthrough for antitumor therapy. However, current attempts to repolarize M2 cells remain limited and are greatly challenged by the hypoxic nature of tumors. Also, the high level of reactive oxygen species (ROS) in the tumor microenvironment (TME) is favorable for the polarization of M2-TAMs. Here, we encapsulated KIRA6, an inhibitor of the IRE1-XBP1 pathway, into a reductive nanoemulsion containing α-tocopherol. Our α-T-K had dual inhibitory effects on the ER stress and oxidative stress. Both in vitro and in vivo experiments suggested that α-T-K effectively reprogrammed M2 macrophages even under hypoxia, achieved by increasing glycolysis and suppressing fatty acid oxidation (FAO). In addition, our data revealed that α-T-K not only delayed tumor growth but elevated the curative effect of PD-1 antibody. Our research demonstrated that simultaneous inhibition of ER stress and oxidative stress could effectively repolarize M2-TAMs under hypoxia, which not only filled the current gap in regulating the biological repolarization of macrophages under hypoxia but provided a meaningful reference for the clinical immunotherapy of sensitized anti-PD-1.
Tumor metastasis is the most dangerous stage in tumorigenesis and its evolution, which causes about 80% clinical death. However, common therapies including chemotherapy may increase the risk of tumor metastasis while killing cancer cells. Tumor metastasis is closely related to many factors in the tumor microenvironment, especially hypoxia. As one of the characteristics of a malignant tumor microenvironment, hypoxia plays an important role in the growth, metabolism, and metastasis of tumors. Upregulation of the hypoxia-inducible factor (HIF) would stimulate the metastasis and migration of cancer cells. In this study, we developed an artificial oxygen carrier system, a hemoglobin-loaded liposome (Hb@lipo), which was capable of effectively delivering oxygen to tumor. The way of providing oxygen not only alleviated tumor hypoxia but also downregulated the expression of HIF, which is conducive to reducing tumor malignancy. Alleviating the tumor hypoxic microenvironment alone is not enough to inhibit tumor metastasis; thus, we prepared the liposome containing a chemotherapeutic agent cabazitaxel (CBZ@lipo). Our data indicated that the combination therapy of Hb@lipo and CBZ@lipo can efficiently kill cancer cells and inhibit tumor growth. At the same time, it can effectively entrap cancer cells in tumor sites by relieving the hypoxic microenvironment of tumors and reduce the metastasis of cancer cells during and after the chemotherapy. Our research may provide a clinical cancer chemotherapy reference that reduces the risk of cancer cell metastasis while inhibiting tumor growth.
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