Riyue Bao, Daniel Stapor, Jason J Luke
BACKGROUND: The T cell-inflamed tumor microenvironment, characterized by CD8 T cells and type I/II interferon transcripts, is an important cancer immunotherapy biomarker. Tumor mutational burden (TMB) may also dictate response, and some oncogenes (i.e., WNT/β-catenin) are known to mediate immunosuppression. METHODS: We performed an integrated multi-omic analysis of human cancer including 11,607 tumors across multiple databases and patients treated with anti-PD1...
October 27, 2020: Genome Medicine
Junyi Che, Adrian Najer, Anna K Blakney, Paul F McKay, Mohamed Bellahcene, Charles W Winter, Amalia Sintou, Jiaqing Tang, Timothy J Keane, Michael D Schneider, Robin J Shattock, Susanne Sattler, Molly M Stevens
Uncontrolled inflammation is a major pathological factor underlying a range of diseases including autoimmune conditions, cardiovascular disease, and cancer. Improving localized delivery of immunosuppressive drugs to inflamed tissue in a non-invasive manner offers significant promise to reduce severe side effects caused by systemic administration. Here, a neutrophil-mediated delivery system able to transport drug-loaded nanocarriers to inflamed tissue by exploiting the inherent ability of neutrophils to migrate to inflammatory tissue is reported...
October 26, 2020: Advanced Materials
Chang-Myung Oh, Hong Jae Chon, Chan Kim
Oncolytic virus (OV) is a new therapeutic strategy for cancer treatment. OVs can selectively infect and destroy cancer cells, and therefore act as an in situ cancer vaccine by releasing tumor-specific antigens. Moreover, they can remodel the tumor microenvironment toward a T cell-inflamed phenotype by stimulating widespread host immune responses against the tumor. Recent evidence suggests several possible applications of OVs against cancer, especially in combination with immune checkpoint inhibitors. In this review, we describe the molecular mechanisms of oncolytic virotherapy and OV-induced immune responses, provide a brief summary of recent preclinical and clinical updates on this rapidly evolving field, and discuss a combinational strategy that is able to overcome the limitations of OV-based monotherapy...
October 19, 2020: International Journal of Molecular Sciences
Christianne Groeneveldt, Priscilla Kinderman, Diana J M van den Wollenberg, Ruben L van den Oever, Jim Middelburg, Dana A M Mustafa, Rob C Hoeben, Sjoerd H van der Burg, Thorbald van Hall, Nadine van Montfoort
BACKGROUND: T-cell-engaging CD3-bispecific antibodies (CD3-bsAbs) are promising modalities for cancer immunotherapy. Although this therapy has reached clinical practice for hematological malignancies, the absence of sufficient infiltrating T cells is a major barrier for efficacy in solid tumors. In this study, we exploited oncolytic reovirus as a strategy to enhance the efficacy of CD3-bsAbs in immune-silent solid tumors. METHODS: The mutant p53 and K-ras induced murine pancreatic cancer model KPC3 resembles human pancreatic ductal adenocarcinomas with a desmoplastic tumor microenvironment, low T-cell density and resistance to immunotherapy...
October 2020: Journal for Immunotherapy of Cancer
Leila Motedayen Aval, James E Pease, Rohini Sharma, David J Pinato
Immune checkpoint inhibitors (ICI) have revolutionised cancer therapy. However, they have been effective in only a small subset of patients and a principal mechanism underlying immune-refractoriness is a 'cold' tumour microenvironment, that is, lack of a T-cell-rich, spontaneously inflamed phenotype. As such, there is a demand to develop strategies to transform the tumour milieu of non-responsive patients to one supporting T-cell-based inflammation. The cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes (cGAS-STING) pathway is a fundamental regulator of innate immune sensing of cancer, with potential to enhance tumour rejection through the induction of a pro-inflammatory response dominated by Type I interferons...
October 16, 2020: Journal of Clinical Medicine
Ryuma Tokunaga, Joanne Xiu, Richard M Goldberg, Philip A Philip, Andreas Seeber, Francesca Battaglin, Hiroyuki Arai, Jae Ho Lo, Madiha Naseem, Alberto Puccini, Martin D Berger, Shivani Soni, Wu Zhang, Sting Chen, Jimmy J Hwang, Anthony F Shields, John L Marshall, Hideo Baba, W Michael Korn, Heinz-Josef Lenz
BACKGROUND: ARID1A is a key subunit of the SWItch/Sucrose Non-Fermentable (SWI/SNF) complex which regulates dynamic repositioning of nucleosomes to repair DNA damage. Only small pilot studies have evaluated the role of ARID1A mutation in colorectal cancer (CRC). The aim of the present study was to explore the potential impact of ARID1A mutation on clinicopathological and molecular characteristics in CRC. METHODS: We used integrated data sets of 7978 CRC cases (one data set from a clinical laboratory improvement amendments [CLIA]-certified laboratory and three independent published data sets)...
October 17, 2020: European Journal of Cancer
Daniela Cerezo-Wallis, Marta Contreras-Alcalde, Kevin Troulé, Xavier Catena, Cynthia Mucientes, Tonantzin G Calvo, Estela Cañón, Cristina Tejedo, Paula C Pennacchi, Sabrina Hogan, Peter Kölblinger, Héctor Tejero, Andrew X Chen, Nuria Ibarz, Osvaldo Graña-Castro, Lola Martinez, Javier Muñoz, Pablo Ortiz-Romero, José L Rodriguez-Peralto, Gonzalo Gómez-López, Fátima Al-Shahrour, Raúl Rabadán, Mitchell P Levesque, David Olmeda, María S Soengas
An open question in aggressive cancers such as melanoma is how malignant cells can shift the immune system to pro-tumorigenic functions. Here we identify midkine (MDK) as a melanoma-secreted driver of an inflamed, but immune evasive, microenvironment that defines poor patient prognosis and resistance to immune checkpoint blockade. Mechanistically, MDK was found to control the transcriptome of melanoma cells, allowing for coordinated activation of nuclear factor-κB and downregulation of interferon-associated pathways...
October 19, 2020: Nature Medicine
Taishi Takahara, Yota Murase, Toyonori Tsuzuki
Although urothelial carcinoma (UC) has been recognised as a homogenous disease entity until recently, it exhibits widely diverse histological variants. Recent studies have revealed that some histological variants may serve as markers of very high risk for advanced cancers and poor prognoses. Certain histological variants can generate a pathological T stage, which may result in unnecessary surgery. Though platinum based chemotherapy is the standard treatment, the use of immune checkpoint inhibitors (ICIs) for UC treatment has become a major trend in oncology...
October 15, 2020: Pathology
Roy S Herbst, Hendrik Tobias Arkenau, Johanna Bendell, Edward Arrowsmith, Martin Wermke, Andres Soriano, Nicolas Penel, Rafael Santana-Davila, Helge Bischoff, Ian Chau, Gu Mi, Hong Wang, Erik Rasmussen, David Ferry, Bo H Chao, Luis Paz-Ares
INTRODUCTION: Data of first-line ramucirumab plus pembrolizumab treatment of programmed death ligand 1 (PD-L1)-positive, non-small cell lung cancer (NSCLC; Cohort E) are reported (NCT02443324). METHODS: In this multicenter, open-label phase 1a/b trial, patients received ramucirumab 10 mg/kg and pembrolizumab 200 mg every 21 days for up to 35 cycles. PD-L1 positivity was defined as tumor proportion score (TPS) ≥1%. Exploratory NanoString biomarker analyses included three T-cell signatures (T-cell-inflamed, Gajewski, and effector T-cells) and CD274 gene expression...
October 14, 2020: Journal of Thoracic Oncology
Ole Gjoerup, Charlotte A Brown, Jeffrey S Ross, Richard S P Huang, Alexa Schrock, James Creeden, David Fabrizio, Khaled Tolba
Immune checkpoint inhibitors (ICPI) have revolutionized cancer therapy and provided clinical benefit to thousands of patients. Despite durable responses in many tumor types, the majority of patients either fail to respond at all or develop resistance to the ICPI. Furthermore, ICPI treatment can be accompanied by serious adverse effects. There is an urgent need for identification of patient populations that will benefit from ICPI as single agents and when used in combinations. As ICPI have achieved regulatory approvals, accompanying biomarkers including PD-L1 immunohistochemistry (IHC) and tumor mutational burden (TMB) have also received approvals for some indications...
October 14, 2020: AAPS Journal
Giuseppe Troiano, Corrado Rubini, Lucrezia Togni, Vito Carlo Alberto Caponio, Khrystyna Zhurakivska, Andrea Santarelli, Nicola Cirillo, Lorenzo Lo Muzio, Marco Mascitti
BACKGROUND: In patients with squamous cell carcinoma of the oral tongue (OTSCC), current tumor node metastasis staging system fails to identify at-risk patients associated with early relapse and poor prognosis despite complete surgical resection. Given the importance of tumor-infiltrating lymphocytes (TILs) in the development of cancers, here we investigated the prognostic significance of the immune phenotype in OTSCC. METHODS: Hematoxylin-eosin stained sections of OTSCCs from 211 patients were evaluated...
October 13, 2020: Cancer Medicine
Jeffrey C Thompson, Christiana Davis, Charuhas Deshpande, Wei-Ting Hwang, Seth Jeffries, Alexander Huang, Tara C Mitchell, Corey J Langer, Steven M Albelda
BACKGROUND: Limited data exist on the role of alterations in HLA Class I antigen processing and presentation machinery in mediating response to immune checkpoint blockade (ICB). METHODS: This retrospective cohort study analyzed transcriptional profiles from pre-treatment tumor samples of 51 chemotherapy-refractory advanced non-small cell lung cancer (NSCLC) patients and two independent melanoma cohorts treated with ICB. An antigen processing machinery (APM) score was generated utilizing eight genes associated with APM ( B2M, CALR, NLRC5, PSMB9, PSME1, PSME3, RFX5, and HSP90AB1 )...
October 2020: Journal for Immunotherapy of Cancer
Riri Kwon, Bong-Ki Hong, Kang-Gu Lee, Eunbyeol Choi, Laurent Sabbagh, Chul-Soo Cho, Naeun Lee, Wan-Uk Kim
BACKGROUND: Clinical efficacy of T cell-based cancer immunotherapy is limited by the lack of T cell infiltration in the tumor mass, especially in solid tumors. Our group demonstrated previously that leukocyte-specific protein 1 (LSP1), an intracellular signal regulator, negatively regulates T cell infiltration in inflamed tissues. METHODS: To determine the immuno-regulatory effects of LSP1 in T cells on tumor progression, we investigated the growth of B16 melanoma in Lsp1 knockout (KO) mice and T cell-specific Lsp1 transgenic (Tg) mice...
October 2020: Journal for Immunotherapy of Cancer
Veronica Stolearenco, Martin R J Namini, Siri S Hasselager, Maria Gluud, Terkild B Buus, Andreas Willerslev-Olsen, Niels Ødum, Thorbjørn Krejsgaard
Cutaneous T-cell lymphoma (CTCL) comprises a group of lymphoproliferative diseases characterized by the accumulation of malignant T cells in chronically inflamed skin lesions. In early stages, the disease presents as skin patches or plaques covering a limited area of the skin and normally follows an indolent course. However, in a subset of patients the cutaneous lesions develop into tumors and the malignant T cells may spread to the lymphatic system, blood and internal organs with fatal consequences. Despite intensive research, the mechanisms driving disease progression remain incompletely understood...
2020: Frontiers in Cell and Developmental Biology
Yanfeng Dai, Xiang Yu, Jianshuang Wei, Fanxin Zeng, Yiran Li, Xiaoquan Yang, Qingming Luo, Zhihong Zhang
Detection of sentinel lymph nodes (SLNs) is critical to guide the treatment of breast cancer. However, distinguishing metastatic SLNs from normal and inflamed lymph nodes (LNs) during surgical resection remains a challenge. Here, we report a CD44 and scavenger receptor class B1 dual-targeting hyaluronic acid nanoparticle (5K-HA-HPPS) loaded with the near-infra-red fluorescent dye DiR-BOA for SLN imaging in breast cancer. The small sized (~40 nm) self-assembled 5K-HA-HPPSs accumulated rapidly in the SLNs after intradermal injection...
2020: Light, Science & Applications
Kevin Fenix, Danushka K Wijesundara, Allison J Cowin, Branka Grubor-Bauk, Zlatko Kopecki
Psoriasis is a common chronic inflammatory skin condition manifested by T cell responses and characterized by preferential recurrence at previously inflamed sites upon withdrawal of treatment. The site-specific disease memory in psoriasis has been linked to CD8+ CD103+ tissue-resident memory T cells (Trm) in the epidermis which were previously thought to only provide "frontline" protection against pathogens and immunosurveillance during cancer development. In this study, we correlated the presence of a subset of the Trm cells which are also CD49a+ with disease severity in human psoriatic lesions with acute and chronic disease...
September 30, 2020: International Journal of Molecular Sciences
Christian Caporuscio, Derek Holmes, Timothy V Olah, Petia Shipkova
Aim: There is little information in the literature regarding assays for measuring CDH17 in tissues. Numerous studies indicate overexpression of CDH17 in a variety of diseases including hepatocellular carcinoma, colorectal and gastric cancer. Here we present an immunoaffinity enrichment LC-MS/MS approach for analysis of CDH17 in human tissues, plasma and serum as well as preclinical models. Results: CDH17 levels were measured in colon and ileum tissues from healthy donors and inflamed tissues from patients with Ulcerative Colitus or Crohn's disease...
October 2, 2020: Bioanalysis
Damien J Zanker, Alex J Spurling, Natasha K Brockwell, Katie L Owen, Jasmine M Zakhour, Tina Robinson, Hendrika M Duivenvoorden, Paul J Hertzog, Stefanie R Mullins, Robert W Wilkinson, Belinda S Parker
Objectives: Loss of tumor-inherent type I interferon (IFN) signalling has been closely linked to accelerated metastatic progression via decreased immunogenicity and antitumor immunity. Previous studies in murine models of triple-negative breast cancer (TNBC) demonstrate that systemic IFN inducers are effective antimetastatic agents, via sustained antitumor CD8+ T-cell responses. Repeated systemic dosing with recombinant IFNs or IFN inducers is associated with significant toxicities; hence, the use of alternate intratumoral agents is an active area of investigation...
2020: Clinical & Translational Immunology
Naoshi Nishida, Kazuko Sakai, Masahiro Morita, Tomoko Aoki, Masahiro Takita, Satoru Hagiwara, Yoriaki Komeda, Mamoru Takenaka, Yasunori Minami, Hiroshi Ida, Kazuomi Ueshima, Kazuto Nishio, Masatoshi Kudo
Background and Aim: Immune checkpoint inhibitors are promising agents for the treatment of hepatocellular carcinomas (HCC) refractory to conventional therapies. To enhance the efficacy of this treatment, immunological and molecular characteristics of HCC with programmed cell death ligand 1 (PD-L1) should be explored. Methods: Clinical backgrounds, PD-L1 expression, and the amount of CD8+ tumor-infiltrating mononuclear cells (TIMCs) were analyzed in 154 HCCs. The expression of 3 stem cell markers and co-inhibitory receptors on tumor cells and TIMCs, respectively, were examined by immunohistochemical analysis...
August 2020: Liver Cancer
Zhenlin Yang, Jiachen Xu, Lin Li, Renda Li, Yalong Wang, Yanhua Tian, Wei Guo, Zhijie Wang, Fengwei Tan, Jianming Ying, Yuchen Jiao, Shugeng Gao, Jie Wang, Yibo Gao, Jie He
Pulmonary sarcomatoid carcinoma (PSC) is a rare subtype of lung cancer with poor prognosis. Here, we perform multi-omics analysis of 56 PSC samples, 14 of which are microdissected to analyze intratumoral heterogeneity. We report the mutational landscape of PSC. The epithelial and sarcomatoid components share numerous genomic alterations, indicating a common progenitor. We find that epithelial-mesenchymal transition (EMT) plays important roles in the carcinogenesis of PSC. The pan-cancer analysis reveals high tumor mutation burden and leukocyte fraction of PSC...
September 28, 2020: Nature Communications
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