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Approximately 50% of patients with surgically resected early-stage lung cancer develop distant metastasis. At present, there is no in vivo metastasis model to investigate the biology of human lung cancer metastases. Using well-characterized lung adenocarcinoma (LUAD) patient-derived organoids (PDOs), we establish an in vivo metastasis model that preserves the biologic features of human metastases. Results of whole-genome and RNA sequencing establish that our in vivo PDO metastasis model can be used to study clonality and tumor evolution and to identify biomarkers related to organotropism. Investigation of the response of KRAS G12C PDOs to sotorasib demonstrates that the model can examine the efficacy of treatments to suppress metastasis and identify mechanisms of drug resistance. Finally, our PDO model cocultured with autologous peripheral blood mononuclear cells can potentially be used to determine the optimal immune-priming strategy for individual patients with LUAD., Competing Interests: Declaration of interests G.R. has financial relationships with Scanlan, AstraZeneca, and Medtronic. S.S. is a member of the AstraZeneca Advisory Board. J.M.I. has stock ownership in LumaCyte and is a consultant/advisory board member for Roche Genentech. M.J.B. is a consultant for AstraZeneca, Iovance Biotherapeutics, and Intuitive Surgical and receives research support from Obsidian Therapeutics. B.T.L. has served as an uncompensated advisor and consultant to Amgen, AstraZeneca, Boehringer Ingelheim, Bolt Biotherapeutics, Daiichi Sankyo, Genentech, and Lilly; has received research grants (institutional) from Amgen, AstraZeneca, Bolt Biotherapeutics, Daiichi Sankyo, Genentech, Hengrui USA, and Lilly; has received academic travel support from Amgen, Jiangsu Hengrui Medicine, and MORE Health; and has intellectual property rights as a book author at Karger Publishers and Shanghai Jiao Tong University Press. M.H.B. receives royalties from Globus Medical and DePuy Synthes. P.S.A. declares research funding from Atara Biotherapeutics; is a scientific advisory board member and consultant for ATARA Biotherapeutics, Bayer, Bio4T2, Carisma Therapeutics, Imugene, ImmPACT Bio, Johnson & Johnson, Orion, and Outpace Bio; has patents, royalties, and intellectual property on mesothelin-targeted chimeric antigen receptor and other T cell therapies, which have been licensed to Atara Biotherapeutics; and has an issued patent method for detection of cancer cells using virus and pending patent applications on PD-1 dominant negative receptor, a wireless pulse-oximetry device, and an ex vivo malignant pleural effusion culture system. MSK has licensed intellectual property related to mesothelin-targeted chimeric antigen receptors and T cell therapies to Atara Biotherapeutics and has associated financial interests. D.R.J. serves on a clinical trial steering committee for AstraZeneca and has research grant support from Merck., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Advances in cancer immunotherapy have transformed cancer care and realized unprecedented responses in many patients. The growing arsenal of novel therapeutics - including immune checkpoint inhibition (ICI), adoptive T cell therapies (ACTs), and cancer vaccines - reflects the success of cancer immunotherapy. The therapeutic benefits of these treatment modalities are generally attributed to the enhanced quantity and quality of antitumor CD8 + T cell responses. Nevertheless, CD4 + T cells are now recognized to play key roles in both the priming and effector phases of the antitumor immune response. In addition to providing T cell help through co-stimulation and cytokine production, CD4 + T cells can also possess cytotoxicity either directly on MHC class II-expressing tumor cells or to other cells within the tumor microenvironment (TME). The presence of specific populations of CD4 + T cells, and their intrinsic plasticity, within the TME can represent an important determinant of clinical response to immune checkpoint inhibitors, vaccines, and chimeric antigen receptor (CAR) T cell therapies. Understanding how the antitumor functions of specific CD4 + T cell types are induced while limiting their protumorigenic attributes will enable more successful immunotherapies., Competing Interests: Declaration of interests L.F. received research funding from Abbvie, Bavarian Nordic, Bristol-Myers Squibb, Dendreon, Janssen, Merck, Nektar, Roche/Genentech, and Parker Institute; served as a consultant to Abbvie, Actym, Amgen, Astra Zeneca, Atreca, Bioatla, Bolt, Bristol Myer Squibb, Crescendo, Daiichi Sankyo, Immunogenesis, Innovent, Merck, NGMBio, Nutcracker, RAPT, Senti, Sutro, and Roche/Genentech; and has ownership interests in Actym, Atreca, Bioatla, Bolt, Immunogenesis, Nutcracker, RAPT, and Senti, unrelated to this review., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

T cell responses are inhibited by acidic environments. T cell receptor (TCR)-induced protein phosphorylation is negatively regulated by dephosphorylation and/or ubiquitination, but the mechanisms underlying sensitivity to acidic environments are not fully understood. Here, we found that TCR stimulation induced a molecular complex of Cbl-b, an E3-ubiquitin ligase, with STS1, a pH-sensitive unconventional phosphatase. The induced interaction depended upon a proline motif in Cbl-b interacting with the STS1 SH3 domain. STS1 dephosphorylated Cbl-b interacting phosphoproteins. The deficiency of STS1 or Cbl-b diminished the sensitivity of T cell responses to the inhibitory effects of acid in an autocrine or paracrine manner in vitro or in vivo. Moreover, the deficiency of STS1 or Cbl-b promoted T cell proliferative and differentiation activities in vivo and inhibited tumor growth, prolonged survival, and improved T cell fitness in tumor models. Thus, a TCR-induced STS1-Cbl-b complex senses intra- or extra-cellular acidity and regulates T cell responses, presenting a potential therapeutic target for improving anti-tumor immunity., Competing Interests: Declaration of interests A.W. is a co-founder and a scientific advisory board (SAB) member of Nurix Therapeutics, Inc., which has a Cbl-b inhibitor in phase I clinical trials. Dr. Weiss has founder shares and receives payment for his role on the Nurix SAB. A.W. also serves on the advisory boards of BlueSphere Bio, BridGene Biologics, EpiBiologics, Genentech, Imidomics, and Jasper Therapeutics. L.F. has received research support from Roche/Genentech, Abbvie, Bavarian Nordic, Bristol Myers Squibb, Dendreon, Janssen, Merck, and Partner Therapeutics. L.F. has served on the SABs of Actym, Astra Zeneca, Atreca, Bioatla, Bolt, Bristol Myer Squibb, Daiichi Sankyo, Immunogenesis, Innovent, Merck, Merck KGA, Nutcracker, RAPT, Scribe, Senti, Sutro, and Roche/Genentech., (Copyright © 2023 Elsevier Inc. All rights reserved.)

In a recent study published in Nature, Kruse et al. demonstrated an indirect tumor-killing mechanism orchestrated by a small number of CD4 + effector T cells. These CD4 + T cells can reprogram myeloid cells not just into IFNγ-induced antigen-presenting cells but also into iNOS-expressing tumoricidal effectors that can eradicate immune-evasive tumors., Competing Interests: Declaration of interests L.F. has received research support from Roche/Genentech, AbbVie, Bavarian Nordic, Bristol Myers Squibb, Dendreon, Janssen, Merck, and Partner Therapeutics. L.F. has served on the scientific advisory boards of Actym, AstraZeneca, Atreca, Bioatla, Bolt, Bristol Myers Squibb, Daiichi Sankyo, Immunogenesis, Innovent, Merck, Merck KGA, Nutcracker, RAPT, Scribe, Senti, Sutro, and Roche/Genentech. K.W. has no interests to declare., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The advent of chimeric antigen receptor (CAR) T cell therapies has transformed the treatment of hematological malignancies; however, broader therapeutic success of CAR T cells has been limited in solid tumors because of their frequently heterogeneous composition. Stress proteins in the MICA and MICB (MICA/B) family are broadly expressed by tumor cells following DNA damage but are rapidly shed to evade immune detection., Methods: We have developed a novel CAR targeting the conserved α3 domain of MICA/B (3MICA/B CAR) and incorporated it into a multiplexed-engineered induced pluripotent stem cell (iPSC)-derived natural killer (NK) cell (3MICA/B CAR iNK) that expressed a shedding-resistant form of the CD16 Fc receptor to enable tumor recognition through two major targeting receptors., Findings: We demonstrated that 3MICA/B CAR mitigates MICA/B shedding and inhibition via soluble MICA/B while simultaneously exhibiting antigen-specific anti-tumor reactivity across an expansive library of human cancer cell lines. Pre-clinical assessment of 3MICA/B CAR iNK cells demonstrated potent antigen-specific in vivo cytolytic activity against both solid and hematological xenograft models, which was further enhanced in combination with tumor-targeted therapeutic antibodies that activate the CD16 Fc receptor., Conclusions: Our work demonstrated 3MICA/B CAR iNK cells to be a promising multi-antigen-targeting cancer immunotherapy approach intended for solid tumors., Funding: Funded by Fate Therapeutics and NIH (R01CA238039)., Competing Interests: Declaration of interests J.G., W.-I.Y., B.H., R.B., T.X., B.-H.Y., C.C., B.G., E.A., M.P., Y.P., H.-Y.C., S.S., L.F., N.B., T.D., M.M., M.D., E.D., J.M., P.S., S.C., T.T.L., R.B., and B.V. are employees and shareholders at Fate Therapeutics. 3MICA/B binder sequence was licensed by Fate Therapeutics from Dana-Farber Cancer Institute. K.W.W. serves on the scientific advisory board of T-Scan Therapeutics, SQZ Biotech, and Nextechinvest and receives sponsored research funding from Novartis. K.W.W. is a co-founder of Immunitas, a biotech company. These activities are not related to the research reported in this publication., (Copyright © 2023 Elsevier Inc. All rights reserved.)

CD8 + T cell responses are critical for anti-tumor immunity. While extensively profiled in the tumor microenvironment, recent studies in mice identified responses in lymph nodes (LNs) as essential; however, the role of LNs in human cancer patients remains unknown. We examined CD8 + T cells in human head and neck squamous cell carcinomas, regional LNs, and blood using mass cytometry, single-cell genomics, and multiplexed ion beam imaging. We identified progenitor exhausted CD8 + T cells (Tpex) that were abundant in uninvolved LN and clonally related to terminally exhausted cells in the tumor. After anti-PD-L1 immunotherapy, Tpex in uninvolved LNs reduced in frequency but localized near dendritic cells and proliferating intermediate-exhausted CD8 + T cells (Tex-int), consistent with activation and differentiation. LN responses coincided with increased circulating Tex-int. In metastatic LNs, these response hallmarks were impaired, with immunosuppressive cellular niches. Our results identify important roles for LNs in anti-tumor immune responses in humans., Competing Interests: Declaration of interests W.E.O’G. and K.B.J. are employees of Genentech/Roche. M.F.K. is senior advisor and founder of Foundery Immune Studios. M.A. is an inventor on patents related to MIBI technology. M.A. is a consultant, board member, and shareholder in Ionpath Inc. M.H.S. is founder and a board member of Teiko.bio and has received a speaking honorarium from Fluidigm Inc. M.F.K., L.F., A.P.A., P.H., and M.H.S. received research funding from Roche/Genentech., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Suppressive myeloid cells can contribute to immunotherapy resistance, but their role in response to checkpoint inhibition (CPI) in anti-PD-1 refractory cancers, such as biliary tract cancer (BTC), remains elusive. We use multiplexed single-cell transcriptomic and epitope sequencing to profile greater than 200,000 peripheral blood mononuclear cells from advanced BTC patients (n = 9) and matched healthy donors (n = 8). Following anti-PD-1 treatment, CD14 + monocytes expressing high levels of immunosuppressive cytokines and chemotactic molecules (CD14 CTX ) increase in the circulation of patients with BTC tumors that are CPI resistant. CD14 CTX can directly suppress CD4 + T cells and induce SOCS3 expression in CD4 + T cells, rendering them functionally unresponsive. The CD14 CTX gene signature associates with worse survival in patients with BTC as well as in other anti-PD-1 refractory cancers. These results demonstrate that monocytes arising after anti-PD-1 treatment can induce T cell paralysis as a distinct mode of tumor-mediated immunosuppression leading to CPI resistance., Competing Interests: Declaration of interests L.F. has received research support (to institution) from Abbvie, Amgen, Bavarian Nordic, Bristol Myers Squibb, Dendreon, Janssen, Merck, Roche/Genentech, and Partner Therapeutics. L.F. has received compensation for serving on the scientific advisory boards (to self) for Actym, Alector, Astra Zeneca, Atreca, Bioatla, Bolt, Bristol Myers Squibb, Immunogenesis, Merck, Merck KGA, Nutcracker, RAPT, Scribe, Senti, Soteria, TeneoBio, and Roche/Genentech. C.J.Y. is a co-founder of Dropprint Genomics, is a Scientific Advisory Board member for and holds equity in Related Sciences and ImmunAI, is a consultant for and holds equity in Maze Therapeutics, is a consultant for TReX Bio, and has received research funding from Genentech. B.K. has received research support (to institution) from Partner Therapeutics. R.K.K. has received research support (to institution) from Agios, Astra Zeneca, Bayer, BMS, Eli Lilly, EMD Serono, Exelixis, Genentech/Roche, Merck, Novartis, Partner Therapeutics, QED, Relay Therapeutics, and Taiho. R.K.K. has received compensation for consulting or IDMC membership from Exact Sciences, Genentech/Roche, and Gilead (to self) and from Agios, Astra Zeneca, BMS, and Merck (to institution)., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Cytotoxic T cells are important effectors of anti-tumor immunity. While tumor killing is ascribed to CD8 + T cell function, pre-clinical and clinical studies have identified intra-tumoral CD4 + T cells that possess cytotoxic programs and can directly kill cancer cells. Cytotoxic CD4 + T cells are found in other disease settings including infection and autoimmunity. Here, we review the phenotypic and functional characteristics of cytotoxic CD4 + T cells in non-cancer and cancer contexts. We conduct a comparative examination of cytolytic mechanisms of cytotoxic CD4 + T cells across disease states and synthesize features that define these cells independent of context. We discuss regulatory mechanisms driving ontogeny and effector function and evidence for the clinical relevance of cytotoxic CD4 + T cells in cancer. In this context, we highlight important gaps in understanding in the biology of cytotoxic CD4 + T cells as well as the potential use of these cells in immunotherapies for specific cancers., Competing Interests: Declaration of interests D.Y.O. has received research support from Merck, PACT Pharma, the Parker Institute for Cancer Immunotherapy, Poseida Therapeutics, TCR2 Therapeutics, Roche/Genentech, and Nutcracker Therapeutics. L.F. has received research support from Abbvie, Amgen, Bavarian Nordic, Bristol Myers Squibb, Corvus, Dendreon, Janssen, Merck, and Roche/Genentech. L.F. also declares serving as a scientific advisory board member to Actym, Allector, AstraZeneca, Atreca, Bioalta, Bolt, Bristol Myers Squibb, Immunogenesis, Innovent, Merck, Merck KGaA, Nutcracker, RAPT, Scribe, Senti, Soteria, Sutro, TeneoBio, and Roche/Genentech., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

T cells mediate anti-tumor immune responses and are the key target of immune checkpoint therapy, but they can also promote immune tolerance. A clear understanding of the specific contributions and biology of different T cell subsets is required to fully harness the curative potential of immunotherapies. Experts discuss the state of the field and key challenges for moving forward., (Copyright © 2021 Elsevier Inc. All rights reserved.)

B cells infiltrate pancreatic ductal adenocarcinoma (PDAC) and in preclinical cancer models, can suppress T cell immunosurveillance in cancer. Here, we conducted a pilot study to assess the safety and feasibility of administering lentiviral-transduced chimeric antigen receptor (CAR)-modified autologous T cells redirected against mesothelin to target tumor cells along with CART cells redirected against CD19 to deplete B cells. Both CARs contained 4-1BB and CD3ζ signaling domains. Three patients with chemotherapy-refractory PDAC received 1.5 g/m 2 cyclophosphamide prior to separate infusions of lentiviral-transduced T cells engineered to express chimeric anti-mesothelin immunoreceptor SS1 (CART-Meso, 3 × 10 7 /m 2 ) and chimeric anti-CD19 immunoreceptor (CART-19, 3 × 10 7 /m 2 ). Treatment was well tolerated without dose-limiting toxicities. Best response was stable disease (1 of 3 patients). CART-19 (compared to CART-Meso) cells showed the greatest expansion in the blood, although persistence was transient. B cells were successfully depleted in all subjects, became undetectable by 7-10 days post-infusion, and remained undetectable for at least 28 days. Together, concomitant delivery of CART-Meso and CART-19 cells in patients with PDAC is safe. CART-19 cells deplete normal B cells but at the dose tested in these 3 subjects did not improve CART-Meso cell persistence., (Copyright © 2020 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.)

Responses to anti-PD-1 immunotherapy occur but are infrequent in bladder cancer. The specific T cells that mediate tumor rejection are unknown. T cells from human bladder tumors and non-malignant tissue were assessed with single-cell RNA and paired T cell receptor (TCR) sequencing of 30,604 T cells from 7 patients. We find that the states and repertoires of CD8 + T cells are not distinct in tumors compared with non-malignant tissues. In contrast, single-cell analysis of CD4 + T cells demonstrates several tumor-specific states, including multiple distinct states of regulatory T cells. Surprisingly, we also find multiple cytotoxic CD4 + T cell states that are clonally expanded. These CD4 + T cells can kill autologous tumors in an MHC class II-dependent fashion and are suppressed by regulatory T cells. Further, a gene signature of cytotoxic CD4 + T cells in tumors predicts a clinical response in 244 metastatic bladder cancer patients treated with anti-PD-L1., Competing Interests: Declaration of Interests D.Y.O. has received research support from Roche/Genentech and Merck and has served as a paid consultant for Maze Therapeutics. L.F. has received research support from Roche/Genentech, Abbvie, Bavarian Nordic, Bristol Myers Squibb, Janssen, and Merck. C.J.Y. is a co-founder of Dropprint Genomics., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Although immunotherapy has proved to be effective in a variety of cancer subtypes, the role of immune checkpoint inhibition in the treatment of prostate cancer remains unclear. Here we review results from the latest clinical trials and discuss data suggesting that certain genetic mutations may confer increased sensitivity to immune checkpoint blockade., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Immune responses in diverse tissue sites are critical for protective immunity and homeostasis. Here, we investigate how tissue localization regulates the development and function of human natural killer (NK) cells, innate lymphocytes important for anti-viral and tumor immunity. Integrating high-dimensional analysis of NK cells from blood, lymphoid organs, and mucosal tissue sites from 60 individuals, we identify tissue-specific patterns of NK cell subset distribution, maturation, and function maintained across age and between individuals. Mature and terminally differentiated NK cells with enhanced effector function predominate in blood, bone marrow, spleen, and lungs and exhibit shared transcriptional programs across sites. By contrast, precursor and immature NK cells with reduced effector capacity populate lymph nodes and intestines and exhibit tissue-resident signatures and site-specific adaptations. Together, our results reveal anatomic control of NK cell development and maintenance as tissue-resident populations, whereas mature, terminally differentiated subsets mediate immunosurveillance through diverse peripheral sites. VIDEO ABSTRACT., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

PD-L1 on the surface of tumor cells binds its receptor PD-1 on effector T cells, thereby suppressing their activity. Antibody blockade of PD-L1 can activate an anti-tumor immune response leading to durable remissions in a subset of cancer patients. Here, we describe an alternative mechanism of PD-L1 activity involving its secretion in tumor-derived exosomes. Removal of exosomal PD-L1 inhibits tumor growth, even in models resistant to anti-PD-L1 antibodies. Exosomal PD-L1 from the tumor suppresses T cell activation in the draining lymph node. Systemically introduced exosomal PD-L1 rescues growth of tumors unable to secrete their own. Exposure to exosomal PD-L1-deficient tumor cells suppresses growth of wild-type tumor cells injected at a distant site, simultaneously or months later. Anti-PD-L1 antibodies work additively, not redundantly, with exosomal PD-L1 blockade to suppress tumor growth. Together, these findings show that exosomal PD-L1 represents an unexplored therapeutic target, which could overcome resistance to current antibody approaches., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Resistance to checkpoint-blockade treatments is a challenge in the clinic. We found that although treatment with combined anti-CTLA-4 and anti-PD-1 improved control of established tumors, this combination compromised anti-tumor immunity in the low tumor burden (LTB) state in pre-clinical models as well as in melanoma patients. Activated tumor-specific T cells expressed higher amounts of interferon-γ (IFN-γ) receptor and were more susceptible to apoptosis than naive T cells. Combination treatment induced deletion of tumor-specific T cells and altered the T cell repertoire landscape, skewing the distribution of T cells toward lower-frequency clonotypes. Additionally, combination therapy induced higher IFN-γ production in the LTB state than in the high tumor burden (HTB) state on a per-cell basis, reflecting a less exhausted immune status in the LTB state. Thus, elevated IFN-γ secretion in the LTB state contributes to the development of an immune-intrinsic mechanism of resistance to combination checkpoint blockade, highlighting the importance of achieving the optimal magnitude of immune stimulation for successful combination immunotherapy strategies., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Multiplexed interrogation of tumor genomic and immune features in serial patient metastases reported in a recent issue of Cell (Angelova et al., 2018) reveals a pivotal role for immune editing in shaping clonal evolution of metastases., (Copyright © 2018 Elsevier Inc. All rights reserved.)

While mutations affecting protein-coding regions have been examined across many cancers, structural variants at the genome-wide level are still poorly defined. Through integrative deep whole-genome and -transcriptome analysis of 101 castration-resistant prostate cancer metastases (109X tumor/38X normal coverage), we identified structural variants altering critical regulators of tumorigenesis and progression not detectable by exome approaches. Notably, we observed amplification of an intergenic enhancer region 624 kb upstream of the androgen receptor (AR) in 81% of patients, correlating with increased AR expression. Tandem duplication hotspots also occur near MYC, in lncRNAs associated with post-translational MYC regulation. Classes of structural variations were linked to distinct DNA repair deficiencies, suggesting their etiology, including associations of CDK12 mutation with tandem duplications, TP53 inactivation with inverted rearrangements and chromothripsis, and BRCA2 inactivation with deletions. Together, these observations provide a comprehensive view of how structural variations affect critical regulators in metastatic prostate cancer., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Regulatory T cells (Tregs) are critical for maintaining immune homeostasis, but their presence in tumor tissues impairs anti-tumor immunity and portends poor prognoses in cancer patients. Here, we reveal a mechanism to selectively target and reprogram the function of tumor-infiltrating Tregs (TI-Tregs) by exploiting their dependency on the histone H3K27 methyltransferase enhancer of zeste homolog 2 (EZH2) in tumors. Disruption of EZH2 activity in Tregs, either pharmacologically or genetically, drove the acquisition of pro-inflammatory functions in TI-Tregs, remodeling the tumor microenvironment and enhancing the recruitment and function of CD8 + and CD4 + effector T cells that eliminate tumors. Moreover, abolishing EZH2 function in Tregs was mechanistically distinct from, more potent than, and less toxic than a generalized Treg depletion approach. This study reveals a strategy to target Tregs in cancer that mitigates autoimmunity by reprogramming their function in tumors to enhance anti-cancer immunity., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Immune responses involve coordination across cell types and tissues. However, studies in cancer immunotherapy have focused heavily on local immune responses in the tumor microenvironment. To investigate immune activity more broadly, we performed an organism-wide study in genetically engineered cancer models using mass cytometry. We analyzed immune responses in several tissues after immunotherapy by developing intuitive models for visualizing single-cell data with statistical inference. Immune activation was evident in the tumor and systemically shortly after effective therapy was administered. However, during tumor rejection, only peripheral immune cells sustained their proliferation. This systemic response was coordinated across tissues and required for tumor eradication in several immunotherapy models. An emergent population of peripheral CD4 T cells conferred protection against new tumors and was significantly expanded in patients responding to immunotherapy. These studies demonstrate the critical impact of systemic immune responses that drive tumor rejection., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The LXR-regulated E3 ubiquitin ligase IDOL controls LDLR receptor stability independent of SREBP and PCSK9, but its relevance to plasma lipid levels is unknown. Here we demonstrate that the effects of the LXR-IDOL axis are both tissue and species specific. In mice, LXR agonist induces Idol transcript levels in peripheral tissues but not in liver, and does not change plasma LDL levels. Accordingly, Idol-deficient mice exhibit elevated LDLR protein levels in peripheral tissues, but not in the liver. By contrast, LXR activation in cynomolgus monkeys induces hepatic IDOL expression, reduces LDLR protein levels, and raises plasma LDL levels. Knockdown of IDOL in monkeys with an antisense oligonucleotide blunts the effect of LXR agonist on LDL levels. These results implicate IDOL as a modulator of plasma lipid levels in primates and support further investigation into IDOL inhibition as a potential strategy for LDL lowering in humans., (Copyright © 2014 Elsevier Inc. All rights reserved.)

CG7870 is a replication-selective oncolytic adenovirus genetically engineered to replicate preferentially in prostate tissue. In a previous phase I/II clinical trial of intraprostatic delivery of CG7870 for locally recurrent prostate cancer this virus was well tolerated. In this phase I study CG7870 was administered as a single intravenous infusion in a group-sequential dose escalation design (1 x 10(10) to 6 x 10(12) viral particles (vp)) to 23 patients with hormone-refractory metastatic prostate cancer. Flulike symptoms (fever, fatigue, rigors, nausea, and/or vomiting) were the most common adverse events. Three therapy-related grade 3 adverse events were reported, one of which (fatigue) was serious. At doses greater than 10(12) vp all five patients experienced asymptomatic grade 1 to 2 transaminitis and/or isolated d-dimer elevations starting on day 2 through 8; dose escalation was therefore halted at 6 x 10(12) vp. All tested patients had CG7870 genomes present in the peripheral blood for at least 90 minutes after infusion; patients in the highest dose group had persistence of genomes through 29 days. A "secondary" or "delayed" peak in plasma CG7870 genome copies (defined as a >10-fold increase in CG7870 genomes from nadir concentration) suggestive of active viral replication and shedding into the bloodstream was detected in 16/23 (70%) patients. CG7870 was detected in the saliva of 3 patients, whereas all urine samples tested negative. All patients developed antibodies to CG7870. Dose-related increases in interleukins 6 and 10 (IL-6, IL-10) blood levels were detected. The peak IL-6 concentration after CG7870 treatment was associated with a transient, asymptomatic decrease in blood pressure. No partial or complete prostate-specific antigen (PSA) responses were observed; however, 5 patients had a decrease in serum PSA of 25% to 49% following a single treatment, including 3 of 8 patients at the highest dose levels.

Recent experiments demonstrate that the concentration of Ca2+ in cytoplasm of Chara corallina internodal cells plays important role in electrical excitation of the plasma membrane. The concentration of free Ca2+ in the cytoplasm -[Ca2+]c is also sensitive to visible light. Both phenomena were simultaneously studied by noninvasive measuring action potential (AP) and magnetic field with a superconducting quantum interference device magnetometer in very close vicinity of electrically excited internodal C. corallina cells. A temporal shift in the depolarization maximum, which progressively occurred after transferring cells from the dark into the light, can be explained by the extended Othmer model. Assuming that the change in membrane voltage during the depolarization part of AP is the direct consequence of an activation of [Ca2+]c sensitive Cl- channels, the model simulations compare well with the experimental data. We can say that we have an example of electrically elicited AP that is of biochemical nature. Electric and magnetic measurements are in good agreement.