Dipeptidyl peptidase 4 inhibition sensitizes radiotherapy by promoting T cell infiltration
Yu TianLingyi KongYan LiZhiyun LiaoXing CaiSuke DengYang XiaoBin ZhangYi‐Jun WangZhanjie ZhangBian WuLu WenFang HuangYan HuChao WanYifei LiaoYajie SunKunyu Yang
4
Citation
29
Reference
10
Related Paper
Citation Trend
Abstract:
Radiotherapy could regulate systemic antitumor immunity, while the immune state in the tumor microenvironment (TME) also affects the efficacy of radiotherapy. We have found that higher CD8+ T cell infiltration is associated with longer overall survival of lung adenocarcinoma and melanoma patients receiving radiotherapy. 8-Gray radiation increased the transcriptional levels of chemokines in tumor cells in vitro. However, it was not sufficient to induce significant lymphocyte infiltration in vivo. Dipeptidyl peptidase 4 (DPP4) has been reported to inactivate chemokines via post-translational truncation. Single-cell sequencing revealed that dendritic cells (DCs) had a higher DPP4 expression among other cells in the TME and upregulated DPP4 expression after radiation. Combining a DPP4 inhibitor with radiotherapy could promote chemokines expression and T cell infiltration in the TME, enhancing the antitumor effect of radiotherapy. Moreover, this therapy further enhanced the therapeutic efficacy of anti-PD-1. In this study, we demonstrated the underlying mechanism of why radiotherapy failed to induce sufficient T cell infiltration and proposed an effective strategy to promote T cell infiltration and sensitize radiotherapy. These findings demonstrate the translational value of DPP4 inhibition as a complementary approach to enhance the efficacy of radiotherapy and the combination of radiotherapy with immunotherapy.Keywords:
Infiltration (HVAC)
Infiltration (HVAC)
Ponding
Infiltrometer
Cite
Citations (9)
Cancer immunotherapy has shown impressive anti-tumor activity in patients with advanced and early-stage malignant tumors, thus improving long-term survival. However, current cancer immunotherapy is limited by barriers such as low tumor specificity, poor response rate, and systemic toxicities, which result in the development of primary, adaptive, or acquired resistance. Immunotherapy resistance has complex mechanisms that depend on the interaction between tumor cells and the tumor microenvironment (TME). Therefore, targeting TME has recently received attention as a feasibility strategy for re-sensitizing resistant neoplastic niches to existing cancer immunotherapy. With the development of nanotechnology, nanoplatforms possess outstanding features, including high loading capacity, tunable porosity, and specific targeting to the desired locus. Therefore, nanoplatforms can significantly improve the effectiveness of immunotherapy while reducing its toxic and side effects on non-target cells that receive intense attention in cancer immunotherapy. This review explores the mechanisms of tumor microenvironment reprogramming in immunotherapy resistance, including TAMs, CAFs, vasculature, and hypoxia. We also examined whether the application of nano-drugs combined with current regimens is improving immunotherapy clinical outcomes in solid tumors.
Cancer Immunotherapy
Reprogramming
Cite
Citations (40)
Modulation of the tumor microenvironment is becoming an increasingly popular research topic in the field of immunotherapy, and studies regarding immune checkpoint blockades and cancer immunotherapy have pushed cancer immunotherapy to a climax. Simultaneously, the manipulation of the immune regulatory pathway can create an effective immunotherapy strategy; however, the tumor microenvironment serves an important role in suppressing the antitumor immunity by its significant heterogeneity. A number of patients with cancer do not have a good response to monotherapy approaches; therefore, combination strategies are required to achieve optimal therapeutic benefits. Targeting the tumor microenvironment may provide a novel strategy for immunotherapy, break down the resistance of conventional cancer therapy and produce the foundation for personalized precision medicine. The present review summarized the research regarding cancer immunotherapy from the perspective of how the tumor microenvironment affects the immune response, with the aim of proposing a novel strategy for cancer immunotherapy and combination therapy.
Cancer Immunotherapy
Immune checkpoint
Cite
Citations (71)
Cite
Citations (20)
Based on unsaturated soil water movement theory,Richards equation be resolved with SWMS-1D software for simulating one-dimensional(1D) soil infiltration under different experiment initial condition.The simulation results of accumulation infiltration quantity and wetting soil movement migration distance were verified by laboratory experiments and it's agreed well with measurement values.It shown that the Richards equation can be studied infiltration characteristic of 1D vertical infiltration.The simulation results was analyzed,it found that the soil texture and soil density have obvious effects on infiltration characteristic of 1D vertical infiltration,the water depth and soil moisture initial content have slight effect on infiltration characteristic,and established the different single parameter power function formula between accumulation infiltration quantity,infiltration speed and wetting soil movement migration distance with infiltration time.
Infiltration (HVAC)
Richards equation
Soil texture
Cite
Citations (2)
Objective To evaluate the clinical application of autologous dendritic tumor vaccination on brain glioma, and to access the alterations of T cell subpopulation in patients with brain glioma before and after autologous immunotherapy. Methods The experimental group (21 Glioma patients) received vaccinations of autologous dendritic cell pulsed with autologous tumor peptides, while the control group (19 glioma patients) only received the regular treatments. Following-ups were carried out and the T cell subpopulations were measured. Results The median survival time of the experimental group (29 months) was significantly longer than that of control group (10 month) (P 0.05). The levels of CD3 + and CD4 + and the ratio of CD4 +/CD8 + ratio in peripheral blood in glioma patients were significantly lower compared with the healthy control, the levels of CD3 +, CD4 +, CD8 +and the CD4 +/CD8 + ratio were significantly increased after immunotherapy than before, but the CD4 +/CD8 + ratio remained lower compared with the healthy control. Conclusion The immune functions of glioma patients were suppressed. Immunotherapy could prolong the survival time of the glioma patient by reconstructing and enhancing some parts of the tumor immunity.
Active immunotherapy
Cite
Citations (0)
Cancer Immunotherapy
Cite
Citations (266)
Tumor immunotherapy is considered to be a novel and promising therapy for tumors and it has recently become a hot research topic. The clinical success of tumor immunotherapy has been notable, but it has been less than totally satisfactory because tumor immunotherapy has performed poorly in numerous patients although it has shown appreciable efficacy in some patients. A minority of patients demonstrate durable responses but the majority of patients do not respond to tumor immunotherapy as the tumor immune microenvironment is different in different patients for different tumor types. The success of tumor immunotherapy may be affected by the heterogeneity of the tumor immune microenvironment and its components, as these vary widely during neoplastic progression. The deepening of research and the development of technology have improved our understanding of the complexity and heterogeneity of the tumor immune microenvironment and its components, and their effects on response to tumor immunotherapy. Therefore, investigating the tumor immune microenvironment and its components and elucidating their association with tumor immunotherapy should improve the ability to study, predict and guide immunotherapeutic responsiveness, and uncover new therapeutic targets.
Cancer Immunotherapy
Tumor progression
Cite
Citations (24)
Successful immunotherapy will require alteration of the tumour microenvironment and/or decreased immune suppression. Tumour-associated macrophages (TAMs) are one major factor affecting tumour microenvironment. We hypothesised that altering TAM phenotype would augment the efficacy of immunotherapy. We and others have reported that 5,6-Dimethylxanthenone-4-acetic-acid (DMXAA, Vadimezan) has the ability to change TAM phenotypes, inducing a tumour microenvironment conducive to antitumour immune responses. We therefore combined DMXAA with active immunotherapies, and evaluated anti-tumour efficacy, immune cell phenotypes (flow cytometry), and tumour microenvironment (RT–PCR). In several different murine models of immunotherapy for lung cancer, DMXAA-induced macrophage activation significantly augmented the therapeutic effects of immunotherapy. By increasing influx of neutrophils and anti-tumour (M1) macrophages to the tumour, DMXAA altered myeloid cell phenotypes, thus changing the intratumoural M2/non-M2 TAM immunoinhibitory ratio. It also altered the tumour microenvironment to be more pro-inflammatory. Modulating macrophages during immunotherapy resulted in increased numbers, activity, and antigen-specificity of intratumoural CD8+ T cells. Macrophage depletion reduced the effect of combining immunotherapy with macrophage activation, supporting the importance of TAMs in the combined effect. Modulating intratumoural macrophages dramatically augmented the effect of immunotherapy. Our observations suggest that addition of agents that activate TAMs to immunotherapy should be considered in future trials.
Augment
Cite
Citations (57)