The lack of response to treatment in most lung cancer patients suggests the value of broadening the benefit of anti–PD-1/PD-L1 monotherapy. Judicious dosing of antiangiogenic agents such as apatinib (VEGFR2-TKI) can modulate the tumor immunosuppressive microenvironment, which contributes to resistance to anti–PD-1/PD-L1 treatment. We therefore hypothesized that inhibiting angiogenesis could enhance the therapeutic efficacy of PD-1/PD-L1 blockade. Here, using a syngeneic lung cancer mouse model, we demonstrated that low-dose apatinib alleviated hypoxia, increased infiltration of CD8+ T cells, reduced recruitment of tumor-associated macrophages in tumor and decreased TGFβ amounts in both tumor and serum. Combining low-dose apatinib with anti–PD-L1 significantly retarded tumor growth, reduced the number of metastases, and prolonged survival in mouse models. Anticancer activity was evident after coadministration of low-dose apatinib and anti–PD-1 in a small cohort of patients with pretreated advanced non–small cell lung cancer. Overall, our work shows the rationale for the treatment of lung cancer with a combination of PD-1/PD-L1 blockade and low-dose apatinib.

Abstract. We are motivated by a recently developed nonlinear inverse scale space method for image denoising [M. Burger, G. Gilboa, S. Osher, and J. Xu, Commun. Math. Sci., 4 (2006) has not yet been studied thoroughly. Earlier total variation models for the multiplicative noise cannot easily be extended to the inverse scale space, due to the lack of global convexity. In this paper, we review existing multiplicative models and present a new total variation framework for the multiplicative noise model, which is globally strictly convex. We extend this convex model to the nonlinear inverse scale space flow and its corresponding relaxed inverse scale space flow. We demonstrate the convergence of the flow for the multiplicative noise model, as well as its regularization effect and its relation to the Bregman distance. We investigate the properties of the flow and study the dependence on flow parameters. The numerical results show an excellent denoising effect and significant improvement over earlier multiplicative models.Key words. inverse scale space, total variation, multiplicative noise, denoising, Bregman distance AMS subject classifications. 35-xx, 65-xx DOI. 10.1137/0706899541. Introduction. Image denoising is an important problem of interest to the mathematical community that has wide application in fields ranging from computer vision to medical imaging. A variety of methods have been proposed over the last decades, including traditional filtering, wavelets, stochastic approaches, and PDE-based variational methods. We refer the reader to [9] for a review of various methods. The additive noise model has been extensively studied, using the Rudin-Osher-Fatemi (ROF) model [23], an iterative regularization method [21], and the inverse scale space (ISS) flow [5,6]. However, the multiplicative noise has not yet been studied thoroughly. In this paper, we obtain a new convex multiplicative noise model and extend it to the nonlinear ISS.

Immune checkpoint inhibitors targeting the programmed cell death receptor/ligand 1 (PD‐1/PD‐L1) pathway have profoundly improved the clinical management of non‐small‐cell lung cancer (NSCLC). Nevertheless, the superiority of single‐agent PD‐1/PD‐L1 inhibitors in pretreated EGFR mutant patients has turned out to be moderate. One proposed mechanism for poor response to immune checkpoint inhibitors is an immunosuppressive tumor microenvironment. Therefore, we utilized two autochthonous EGFR‐driven lung tumor models to investigate dynamic microenvironmental responses to EGFR‐TKI treatment. We observed that at an early stage, sensitive EGFR‐TKIs caused obvious tumor shrinkage accompanied by increased cytotoxic CD8+ T cells and dendritic cells, eradication of Foxp3+ Tregs, and inhibition of M2‐like polarization of macrophages. However, the tumor microenvironmental changes that may be most beneficial for combination treatment with immune‐mediated anticancer approaches were only temporary and disappeared as treatment continued. Meanwhile, the level of myeloid‐derived suppressor cells (MDSCs), particularly mononuclear MDSCs, was consistently elevated throughout the treatment. Analysis of inflammatory factors in serum showed that EGFR‐TKIs increased the levels of IL‐10 and CCL‐2. Our study systematically analyzed dynamic changes in tumor microenvironments responding to EGFR‐TKIs in vivo. The results have implications for combination therapy using EGFR‐TKIs. The optimal sequence of the treatment and strategies that modulate the tumor microenvironment to a state that may favor antitumor immune responses need to be considered when designing clinical trials.