Significance: PD-1 blockade is a cancer immunotherapy effective in various types of cancer. However, we observed rapid cancer progression, called hyperprogressive disease (HPD), in ∼10% of advanced gastric cancer patients treated with anti–PD-1 monoclonal antibody. Tumors of HPD patients possessed highly proliferating FoxP3⁺Treg cells after treatment, contrasting with their reduction in non-HPD tumors. In vitro PD-1 blockade augmented proliferation and suppressive activity of human Treg cells. Likewise, murine Treg cells that were deficient in PD-1 signaling were more proliferative and immunosuppressive. Thus, HPD may occur when PD-1 blockade activates and expands tumor-infiltrating PD-1⁺Treg cells to overwhelm tumor-reactive PD-1⁺effector T cells. Depletion of the former may therefore help treat and prevent HPD.

Vascular pericytes, an important cellular component in the tumor microenvironment, are often associated with tumor vasculatures, and their functions in cancer invasion and metastasis are poorly understood. Here we show that PDGF-BB induces pericyte–fibroblast transition (PFT), which significantly contributes to tumor invasion and metastasis. Gain- and loss-of-function experiments demonstrate that PDGF-BB-PDGFRβ signaling promotes PFT both in vitro and in in vivo tumors. Genome-wide expression analysis indicates that PDGF-BB–activated pericytes acquire mesenchymal progenitor features. Pharmacological inhibition and genetic deletion of PDGFRβ ablate the PDGF-BB–induced PFT. Genetic tracing of pericytes with two independent mouse strains, TN-AP-CreERT2:R26R-tdTomato and NG2-CreERT2:R26R-tdTomato, shows that PFT cells gain stromal fibroblast and myofibroblast markers in tumors. Importantly, coimplantation of PFT cells with less-invasive tumor cells in mice markedly promotes tumor dissemination and invasion, leading to an increased number of circulating tumor cells and metastasis. Our findings reveal a mechanism of vascular pericytes in PDGF-BB–promoted cancer invasion and metastasis by inducing PFT, and thus targeting PFT may offer a new treatment option of cancer metastasis. Significance We show that vascular pericytes significantly contribute to cancer invasion and metastasis by the mechanism of the pericyte–fibroblast transition (PFT). This study proposes this concept and indicates the vascular pericyte’s role. Vascular pericytes were considered to remodel tumor vessels toward a mature phenotype. However, once dissociated from tumor vessels their functions within the tumor tissue are not known. In the present study, we show that pericytes, once detached from tumor microvasculatures, underwent differentiation to become stromal fibroblasts, which are known to contribute to tumor invasion and metastasis. Our results show that vascular pericytes are the important source of stromal fibroblasts and targeting PFT may offer a new treatment option in cancer metastasis.

In the FANTOM5 project, transcription initiation events across the human and mouse genomes were mapped at a single base-pair resolution and their frequencies were monitored by CAGE (Cap Analysis of Gene Expression) coupled with single-molecule sequencing. Approximately three thousands of samples, consisting of a variety of primary cells, tissues, cell lines, and time series samples during cell activation and development, were subjected to a uniform pipeline of CAGE data production. The analysis pipeline started by measuring RNA extracts to assess their quality, and continued to CAGE library production by using a robotic or a manual workflow, single molecule sequencing, and computational processing to generate frequencies of transcription initiation. Resulting data represents the consequence of transcriptional regulation in each analyzed state of mammalian cells. Non-overlapping peaks over the CAGE profiles, approximately 200,000 and 150,000 peaks for the human and mouse genomes, were identified and annotated to provide precise location of known promoters as well as novel ones, and to quantify their activities.