Table of Contents
Jan 2017
Volume 27, Issue 1, Page 1-160
About the Cover:  
Rong-Fu Wang1,2,3
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A century ago, Paul Ehrlich postulated that cancer would be quite common in long-lived organisms if not for the protective effects of immunity. Harnessing the immune system to treat cancer can be traced back to William Coley, a surgeon at Cornell University, who treated cancer patients with live bacteria in 1896. In 1980s, Steven Rosenberg and his colleagues developed adoptive cell therapy (ACT) using tumor-infiltrating lymphocytes (TILs) for the treatment of melanoma cancer patients1, providing the first direct evidence that the immune system can be manipulated to achieve therapeutic efficacy in cancer treatment. Despite significant progresses made before 2010, many clinical studies were met only with sporadic success, leading to the disbelief in most people that cancer immunotherapy can effectively treat cancer.
Deborah Charlesworth1
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Cytoplasmic male sterility (CMS) factors have long been known in some wild plants, and also in some domesticated species, where they are used to produce plants to be used as maternal parents, for example to breed hybrids that display hybrid vigor. Their origins have been mystifying, and now a study recently published in Cell Research helps understand how one widely-used rice CMS factor evolved.
  Research Highlight
Maurizio Renna1 and David C Rubinsztein1
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A recent study makes the surprising observation that autophagosomes can still form in the absence of the core conjugation machinery. Furthermore, while such autophagosomes can fuse with lysosomes, their degradation is delayed, and this is associated with delayed destruction of the inner autophagosomal double membrane, highlighting a new role for proteins thought to act exclusively in the formation of autophagosomes in late stages of the autophagic itinerary within autolysosomes.
Percy A Knolle1
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Studying the immune response against infection with hepatitis viruses is hampered by the lack of suitable preclinical model systems. A recent publication in Science identifies the cytosolic adapter molecule MAVS as being responsible for species restriction of infection with hepatitis A virus as well as linking cytosolic immune sensing in infected hepatocytes with innate effector functions and protective adaptive immunity.
Peilin Ma1, Weihua Song1 and Jay L Hess1
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Despite major advances in understanding the genetics and epigenetics of acute myelogenous leukemia, there is still a great need to develop more specific and effective therapies. High throughput approaches involving either genetic approaches or small molecule inhibitor screens are beginning to identify promising new therapeutic targets.
Rong-Fu Wang1,2,3 and Helen Y Wang1
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Harnessing the immune system to eradicate malignant cells is becoming a most powerful new approach to cancer therapy. FDA approval of the immunotherapy-based drugs, sipuleucel-T (Provenge), ipilimumab (Yervoy, anti-CTLA-4), and more recently, the programmed cell death (PD)-1 antibody (pembrolizumab, Keytruda), for the treatment of multiple types of cancer has greatly advanced research and clinical studies in the field of cancer immunotherapy. Furthermore, recent clinical trials, using NY-ESO-1-specific T cell receptor (TCR) or CD19-chimeric antigen receptor (CAR), have shown promising clinical results for patients with metastatic cancer. Current success of cancer immunotherapy is built upon the work of cancer antigens and co-inhibitory signaling molecules identified 20 years ago. Among the large numbers of target antigens, CD19 is the best target for CAR T cell therapy for blood cancer, but CAR-engineered T cell immunotherapy does not yet work in solid cancer. NY-ESO-1 is one of the best targets for TCR-based immunotherapy in solid cancer. Despite the great success of checkpoint blockade therapy, more than 50% of cancer patients fail to respond to blockade therapy. The advent of new technologies such as next-generation sequencing has enhanced our ability to search for new immune targets in onco-immunology and accelerated the development of immunotherapy with potentially broader coverage of cancer patients. In this review, we will discuss the recent progresses of cancer immunotherapy and novel strategies in the identification of new immune targets and mutation-derived antigens (neoantigens) for cancer immunotherapy and immunoprecision medicine.
Laura A Johnson1 and Carl H June1
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Chimeric antigen receptor (CAR) gene-engineered T cell therapy holds the potential to make a meaningful difference in the lives of patients with terminal cancers. For decades, cancer therapy was based on biophysical parameters, with surgical resection to debulk, followed by radiation and chemotherapy to target the rapidly growing tumor cells, while mostly sparing quiescent normal tissues. One breakthrough occurred with allogeneic bone-marrow transplant for patients with leukemia, which provided a sometimes curative therapy. The field of adoptive cell therapy for solid tumors was established with the discovery that tumor-infiltrating lymphocytes could be expanded and used to treat and even cure patients with metastatic melanoma. Tumor-specific T-cell receptors (TCRs) were identified and engineered into patient peripheral blood lymphocytes, which were also found to treat tumors. However, these were limited by patient HLA-restriction. Close behind came generation of CAR, combining the exquisite recognition of an antibody with the effector function of a T cell. The advent of CD19-targeted CARs for treating patients with multiple forms of advanced B-cell malignancies met with great success, with up to 95% response rates. Applying CAR treatment to solid tumors, however, has just begun, but already certain factors have been made clear: the tumor target is of utmost importance for clinicians to do no harm; and solid tumors respond differently to CAR therapy compared with hematologic ones. Here we review the state of clinical gene-engineered T cell immunotherapy, its successes, challenges, and future.
Haruko Tashiro1 and Malcolm K Brenner1
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Approximately 12% of all cancers worldwide are associated with viral infections. To date, eight viruses have been shown to contribute to the development of human cancers, including Epstein-Barr virus (EBV), Hepatitis B and C viruses, and Human papilloma virus, among others. These DNA and RNA viruses produce oncogenic effects through distinct mechanisms. First, viruses may induce sustained disorders of host cell growth and survival through the genes they express, or may induce DNA damage response in host cells, which in turn increases host genome instability. Second, they may induce chronic inflammation and secondary tissue damage favoring the development of oncogenic processes in host cells. Viruses like HIV can create a more permissive environment for cancer development through immune inhibition, but we will focus on the previous two mechanisms in this review. Unlike traditional cancer therapies that cannot distinguish infected cells from non-infected cells, immunotherapies are uniquely equipped to target virus-associated malignancies. The targeting and functioning mechanisms associated with the immune response can be exploited to prevent viral infections by vaccination, and can also be used to treat infection before cancer establishment. Successes in using the immune system to eradicate established malignancy by selective recognition of virus-associated tumor cells are currently being reported. For example, numerous clinical trials of adoptive transfer of ex vivo generated virus-specific T cells have shown benefit even for established tumors in patients with EBV-associated malignancies. Additional studies in other virus-associated tumors have also been initiated and in this review we describe the current status of immunotherapy for virus-associated malignancies and discuss future prospects.
Rachel L Sabado1, Sreekumar Balan1 and Nina Bhardwaj1
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Immunotherapy using dendritic cell (DC)-based vaccination is an approved approach for harnessing the potential of a patient's own immune system to eliminate tumor cells in metastatic hormone-refractory cancer. Overall, although many DC vaccines have been tested in the clinic and proven to be immunogenic, and in some cases associated with clinical outcome, there remains no consensus on how to manufacture DC vaccines. In this review we will discuss what has been learned thus far about human DC biology from clinical studies, and how current approaches to apply DC vaccines in the clinic could be improved to enhance anti-tumor immunity.
Leticia Corrales1,*, Vyara Matson1,*, Blake Flood1, Stefani Spranger1 and Thomas F Gajewski1,2
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A pre-existing T cell-inflamed tumor microenvironment has prognostic utility and also can be predictive for response to contemporary cancer immunotherapies. The generation of a spontaneous T cell response against tumor-associated antigens depends on innate immune activation, which drives type I interferon (IFN) production. Recent work has revealed a major role for the STING pathway of cytosolic DNA sensing in this process. This cascade of events contributes to the activation of Batf3-lineage dendritic cells (DCs), which appear to be central to anti-tumor immunity. Non-T cell-inflamed tumors lack chemokines for Batf3 DC recruitment, have few Batf3 DCs, and lack a type I IFN gene signature, suggesting that failed innate immune activation may be the ultimate cause for lack of spontaneous T cell activation and accumulation. With this information in hand, new strategies for triggering innate immune activation and Batf3 DC recruitment are being developed, including novel STING agonists for de novo immune priming. Ultimately, the successful development of effective innate immune activators should expand the fraction of patients that can respond to immunotherapies, such as with checkpoint blockade antibodies.
Atsushi Tanaka1,2 and Shimon Sakaguchi1
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FOXP3-expressing regulatory T (Treg) cells, which suppress aberrant immune response against self-antigens, also suppress anti-tumor immune response. Infiltration of a large number of Treg cells into tumor tissues is often associated with poor prognosis. There is accumulating evidence that the removal of Treg cells is able to evoke and enhance anti-tumor immune response. However, systemic depletion of Treg cells may concurrently elicit deleterious autoimmunity. One strategy for evoking effective tumor immunity without autoimmunity is to specifically target terminally differentiated effector Treg cells rather than all FOXP3+ T cells, because effector Treg cells are the predominant cell type in tumor tissues. Various cell surface molecules, including chemokine receptors such as CCR4, that are specifically expressed by effector Treg cells can be the candidates for depleting effector Treg cells by specific cell-depleting monoclonal antibodies. In addition, other immunological characteristics of effector Treg cells, such as their high expression of CTLA-4, active proliferation, and apoptosis-prone tendency, can be exploited to control specifically their functions. For example, anti-CTLA-4 antibody may kill effector Treg cells or attenuate their suppressive activity. It is hoped that combination of Treg-cell targeting (e.g., by reducing Treg cells or attenuating their suppressive activity in tumor tissues) with the activation of tumor-specific effector T cells (e.g., by cancer vaccine or immune checkpoint blockade) will make the current cancer immunotherapy more effective.
Miao Gui1,*, Wenfei Song2,*, Haixia Zhou2, Jingwei Xu1, Silian Chen1, Ye Xiang1 and Xinquan Wang2,3
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The global outbreak of SARS in 2002-2003 was caused by the infection of a new human coronavirus SARS-CoV. The infection of SARS-CoV is mediated mainly through the viral surface glycoproteins, which consist of S1 and S2 subunits and form trimer spikes on the envelope of the virions. Here we report the ectodomain structures of the SARS-CoV surface spike trimer in different conformational states determined by single-particle cryo-electron microscopy. The conformation 1 determined at 4.3 Å resolution is three-fold symmetric and has all the three receptor-binding C-terminal domain 1 (CTD1s) of the S1 subunits in “down” positions. The binding of the “down” CTD1s to the SARS-CoV receptor ACE2 is not possible due to steric clashes, suggesting that the conformation 1 represents a receptor-binding inactive state. Conformations 2-4 determined at 7.3, 5.7 and 6.8 Å resolutions are all asymmetric, in which one RBD rotates away from the “down” position by different angles to an “up” position. The “up” CTD1 exposes the receptor-binding site for ACE2 engagement, suggesting that the conformations 2-4 represent a receptor-binding active state. This conformational change is also required for the binding of SARS-CoV neutralizing antibodies targeting the CTD1. This phenomenon could be extended to other betacoronaviruses utilizing CTD1 of the S1 subunit for receptor binding, which provides new insights into the intermediate states of coronavirus pre-fusion spike trimer during infection.
Huiwu Tang1,2,3, Xingmei Zheng1,2,3, Chuliang Li1,2,3, Xianrong Xie1,2,3, Yuanling Chen1,2,3, Letian Chen1,2,3,4, Xiucai Zhao1,2,3, Huiqi Zheng1,2,3, Jiajian Zhou1,2,3, Shan Ye1,2,3, Jingxin Guo1,2,3 and Yao-Guang Liu1,2,3
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New gene origination is a major source of genomic innovations that confer phenotypic changes and biological diversity. Generation of new mitochondrial genes in plants may cause cytoplasmic male sterility (CMS), which can promote outcrossing and increase fitness. However, how mitochondrial genes originate and evolve in structure and function remains unclear. The rice Wild Abortive type of CMS is conferred by the mitochondrial gene WA352c (previously named WA352) and has been widely exploited in hybrid rice breeding. Here, we reconstruct the evolutionary trajectory of WA352c by the identification and analyses of 11 mitochondrial genomic recombinant structures related to WA352c in wild and cultivated rice. We deduce that these structures arose through multiple rearrangements among conserved mitochondrial sequences in the mitochondrial genome of the wild rice Oryza rufipogon, coupled with substoichiometric shifting and sequence variation. We identify two expressed but nonfunctional protogenes among these structures, and show that they could evolve into functional CMS genes via sequence variations that could relieve the self-inhibitory potential of the proteins. These sequence changes would endow the proteins the ability to interact with the nucleus-encoded mitochondrial protein COX11, resulting in premature programmed cell death in the anther tapetum and male sterility. Furthermore, we show that the sequences that encode the COX11-interaction domains in these WA352c-related genes have experienced purifying selection during evolution. We propose a model for the formation and evolution of new CMS genes via a “multi-recombination/protogene formation/functionalization” mechanism involving gradual variations in the structure, sequence, copy number, and function.
Zhenkun Na1, Siok Ping Yeo2, Sakshibeedu R Bharath1, Matthew W Bowler4,5, Esra Balıkçı1, Cheng-I Wang2 and Haiwei Song1,3
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PD-1 is a type I immune inhibitory transmembrane receptor of the CD28 family that modulates the activity of T cells in peripheral tissues1. It is expressed in T cells, B cells, monocytes, natural killer cells and many tumor-infiltrating lymphocytes2. Binding of PD-1 to its ligands PD-L1 and PD-L2 reduces T-cell activity3.
Kefang Liu1,2,*, Shuguang Tan3,*, Yan Chai3, Danqing Chen3, Hao Song4, Catherine Wei-Hong Zhang5, Yi Shi3, Jun Liu1,2, Wenjie Tan1,2, Jianxin Lyu1, Shan Gao6, Jinghua Yan7, Jianxun Qi3 and George F Gao1,2,3
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Monoclonal antibodies (mAbs) blocking immune checkpoint molecules, especially programmed cell death 1 (PD-1) and its ligands programmed cell death 1 ligand 1 (PD-L1) and ligand 2 (PD-L2), are currently been investigated for treatment of various tumors1,2,3. PD-L1 and PD-L2 are usually upregulated on the surface of multiple tumor cells to mediate immune tolerance through the interaction with inhibitory PD-1 molecule4.
Xiaojuan Liu1,*, Yongping Zhang2,*, Chen Cheng1,3,*, Albert W Cheng4, Xingying Zhang1,5, Na Li1, Changqing Xia2,6, Xiaofei Wei7, Xiang Liu1 and Haoyi Wang1,5,8
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Chimeric antigen receptor (CAR) T cell therapy is a promising approach to treat cancer, such as B-cell malignancy1. However, the current standard treatment requires autologous adoptive cell transfer, which is expensive and time-consuming. For newborn and elder patients, it is often difficult to obtain enough T cells with good quality to generate patient-specific CAR-T cells. To make CAR-T therapy more accessible, it is highly desirable to develop an allogeneic adoptive transfer strategy, in which universal CAR-T cells derived from T cells from healthy donors can be applied to treat multiple patients. For this strategy to work, the αβ T-cell receptor (TCR) on allogeneic CAR-T cells needs to be eliminated to avoid graft-versus-host-disease (GVHD), and human leukocyte antigens class I (HLA-Is) on CAR-T cells need to be removed to minimize their immunogenicity. Previous studies have shown that mutation in TCRα subunit constant (TRAC) leads to loss of αβ TCR on T-cell surface2, and beta-2 microglobulin (B2M) is essential for cell-surface expression of HLA-I heterodimers3.
Shuo Wang1,2,*, Shuai Hong1,2,*, Yong-Qiang Deng3,*, Qing Ye3, Ling-Zhai Zhao4, Fu-Chun Zhang4, Cheng-Feng Qin3 and Zhiheng Xu1,5
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Zika virus (ZIKV) is spreading rapidly around the world in over 60 countries. There is a mounting concern over the association of ZIKV infection and devastating cases of fetal and newborn microcephaly cases1. The connection between ZIKV infection and microcephaly was first proposed based on the presence of ZIKV in microcephalic fetal brain tissues1. The causal link between ZIKV infection and microcephaly was recently confirmed in animal models and human cerebral organoids2,3,4. The infection is likely to cause deregulation of genes related to neural progenitor cell (NPC) development, cell death and immune response, and subsequently microcephaly2,3,4.



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