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UAV trajectory prediction is the core technology for autonomous UAV flight and is a prerequisite for control and navigation. In this article, the UAV flight path prediction model is established by collecting the flight data of the actual UAV. First, the UAV flight information collection and data preprocessing are carried out; second, the UAV flight state recognition model is established based on the PCA-SVM model to identify five UAV flight states; and finally, the flight path prediction model of UAV based on flight state recognition is established, and the neural network model is established based on the flight path of five flight state recognition. The experimental results show that: first, the accuracy of UAV flight state recognition based on PCA-SVM is more than 90%; second, the average prediction error of the traditional neural network UAV trajectory is 0.422 m, and the maximum error of the circling state is 0.84 m; and third, the average prediction error of the UAV flight path based on flight state recognition is 0.214 m, and the maximum error of the circling state is 0.41 m. The model error is less than 0.5 m. The results show that the prediction model with flight state recognition has significantly less error than the direct UAV trajectory prediction, and the prediction model with flight state recognition predicts better than the traditional unscented Kalman filter method.

Immune checkpoint blockade (ICB)-based immunotherapy depends on functional tumour-infiltrating lymphocytes (TILs), but essential cytokines are less understood. Here we uncover an essential role of endogenous IL-2 for ICB responsiveness and the correlation between insufficient IL-2 signalling and T-cell exhaustion as tumours progress. To determine if exogenous IL-2 in the tumour microenvironment can overcome ICB resistance, we engineered mesenchymal stem cells (MSCs) to successfully deliver IL-2 mutein dimer (SIL2-EMSC) to TILs. While MSCs have been used to suppress inflammation, SIL2-EMSCs elicit anti-tumour immunity and overcome ICB resistance without toxicity. Mechanistically, SIL2-EMSCs activate and expand pre-existing CD8+TILs, sufficient for tumour control and induction of systemic anti-tumour effects. Furthermore, engineered MSCs create synergy of innate and adaptive immunity. The therapeutic benefits of SIL2-EMSCs were also observed in humanized mouse models. Overall, engineered MSCs rejuvenate CD8+TILs and thus potentiate ICB and chemotherapy.

Recently, immune checkpoint blockade (ICB), especially anti-programmed death 1 (anti-PD-1) and anti-programmed death-ligand 1 (anti-PD-L1) therapy, has become an increasingly appealing therapeutic strategy for cancer patients. However, only a small portion of patients responds to anti-PD treatment. Therefore, treatment strategies are urgently needed to reverse the ICB-resistant tumor microenvironment (TME). It has become clear that the TME has diminished innate sensing that is critical to activate adaptive immunity. In addition, tumor cells upregulate various immunosuppressive factors to diminish the immune response and resist immunotherapy. In this review, we briefly update the current small molecular drugs that could synergize with immunotherapy, especially anti-PD therapy. We will discuss the modes of action by those drugs including inducing innate sensing and limiting immunosuppressive factors in the TME.

High-dose radiation activates caspases in tumor cells to produce abundant DNA fragments for DNA sensing in antigen-presenting cells, but the intrinsic DNA sensing in tumor cells after radiation is rather limited. Here we demonstrate that irradiated tumor cells hijack caspase 9 signaling to suppress intrinsic DNA sensing. Instead of apoptotic genomic DNA, tumor-derived mitochondrial DNA triggers intrinsic DNA sensing. Specifically, loss of mitochondrial DNA sensing in Casp9−/−tumors abolishes the enhanced therapeutic effect of radiation. We demonstrated that combining emricasan, a pan-caspase inhibitor, with radiation generates synergistic therapeutic effects. Moreover, loss of CASP9 signaling in tumor cells led to adaptive resistance by upregulating programmed death-ligand 1 (PD-L1) and resulted in tumor relapse. Additional anti-PD-L1 blockade can further overcome this acquired immune resistance. Therefore, combining radiation with a caspase inhibitor and anti-PD-L1 can effectively control tumors by sequentially blocking both intrinsic and extrinsic inhibitory signaling.

Notch pathways have important roles in carcinogenesis including pathways involving the Notch1 and Notch2 oncogenes. Pan-Notch inhibitors, such as gamma secretase inhibitors (GSIs), have been used in the clinical trials, but the outcomes of these trials have been insufficient and have yielded unclear. In the present study, we demonstrated that GSIs, such as MK-0752 and RO4929097, inhibit breast tumor growth, but increase the breast cancer stem cell (BCSC) population in Notch3-expressing breast cancer cells, in a process that is coupled with IL6 induction and is blocked by the IL6R antagonist Tocilizumab (TCZ). IL6 induction results from inhibition of Notch3-Hey2 signaling through MK-0752. Furthermore, HIF1a upregulates Notch3 expression via direct binding to the Notch3 promoter and subsequently downregulates BCSCs by decreasing the IL6 levels in Notch3-expressing breast cancer cells. Utilizing both breast cancer cell line xenografts and patient-derived xenografts (PDX), we showed that the combination of MK-0752 and Tocilizumab significantly decreases BCSCs and inhibits tumor growth and thus might serve as a novel therapeutic strategy for treating women with Notch3-expressing breast cancers.

A population of partially exhausted CXCR5+CD8+T cells, induced by chronic virus infection and residing in B-cell follicles, is shown to control viral replication.

Mutations in STK11/LKB1in non-small cell lung cancer (NSCLC) are associated with poor patient responses to immune checkpoint blockade (ICB), and introduction of a Stk11/Lkb1(L) mutation into murine lung adenocarcinomas driven by mutant Krasand Trp53loss (KP) resulted in an ICB refractory syngeneic KPLtumor. Mechanistically this occurred because KPLmutant NSCLCs lacked TCF1-expressing CD8 T cells, a phenotype recapitulated in human STK11/LKB1mutant NSCLCs. Systemic inhibition of Axl results in increased type I interferon secretion from dendritic cells that expanded tumor-associated TCF1+PD-1+CD8 T cells, restoring therapeutic response to PD-1 ICB in KPLtumors. This was observed in syngeneic immunocompetent mouse models and in humanized mice bearing STK11/LKB1mutant NSCLC human tumor xenografts. NSCLC-affected individuals with identified STK11/LKB1mutations receiving bemcentinib and pembrolizumab demonstrated objective clinical response to combination therapy. We conclude that AXL is a critical targetable driver of immune suppression in STK11/LKB1mutant NSCLC.

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An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Nature 537, 412–428 (2016); doi:10.1038/nature19317 In this Letter, owing to errors introduced by the typesetters, ‘CXCR5+’ should have been ‘CXCR5−’ at two places in the Abstract, to read as follows: “…more potent cytotoxicity than the CXCR5− subset…” and “…greater therapeutic potential than the CXCR5− subset …”.