Journal Articles

Elevated serum interleukin-8 is associated with enhanced intratumor neutrophils and reduced clinical benefit of immune-checkpoint inhibitors

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Analyzing data from various clinical trials of PD-1/PD-L1 checkpoint blockade (sometimes in combination with CTLA-4 checkpoint blockade), Schalper and Carleton et al. found that IL-8 serves as an independent biomarker that predicts shorter survival and reduced clinical benefit from immunotherapy. Their data suggest that IL-8 likely recruits immunosuppressive myeloid cells like neutrophils and macrophages to tumors, resulting in tumor environments that exclude T cells and/or suppress T cell activation.

Analyzing data from various clinical trials of PD-1/PD-L1 checkpoint blockade (sometimes in combination with CTLA-4 checkpoint blockade), Schalper and Carleton et al. found that IL-8 serves as an independent biomarker that predicts shorter survival and reduced clinical benefit from immunotherapy. Their data suggest that IL-8 likely recruits immunosuppressive myeloid cells like neutrophils and macrophages to tumors, resulting in tumor environments that exclude T cells and/or suppress T cell activation.

ABSTRACT: Serum interleukin-8 (IL-8) levels and tumor neutrophil infiltration are associated with worse prognosis in advanced cancers. Here, using a large-scale retrospective analysis, we show that elevated baseline serum IL-8 levels are associated with poor outcome in patients (n = 1,344) with advanced cancers treated with nivolumab and/or ipilimumab, everolimus or docetaxel in phase 3 clinical trials, revealing the importance of assessing serum IL-8 levels in identifying unfavorable tumor immunobiology and as an independent biomarker in patients receiving immune-checkpoint inhibitors.

Author Info: (1)Department of Pathology, Yale University School of Medicine, New Haven, CT, USA. kurt.schalper@yale.edu. (2)Department of Translational Medicine, Bristol-Myers Squibb, Princeton

Author Info: (1)Department of Pathology, Yale University School of Medicine, New Haven, CT, USA. kurt.schalper@yale.edu. (2)Department of Translational Medicine, Bristol-Myers Squibb, Princeton, NJ, USA. (3)Department of Global Biometric Sciences, Bristol-Myers Squibb, Princeton, NJ, USA. (4)Department of Translational Bioinformatics, Bristol-Myers Squibb, Princeton, NJ, USA. (5)Department of Research and Early Development, Bristol-Myers Squibb, Princeton, NJ, USA. (6)Department of Pathology, Yale University School of Medicine, New Haven, CT, USA. (7)Department of Biostatistics, School of Public Health, Yale University, New Haven, CT, USA. (8)Oncology Department, Clinica Universidad de Navarra, Pamplona, Spain. (9)Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain. (10)Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA. (11)Department of Immunology and Immunotherapy, Centro de Investigación Médica Aplicada (CIMA), Universidad de Navarra, Pamplona, Spain. (12)Oncology Department, Clinica Universidad de Navarra, Pamplona, Spain. imelero@unav.es. (13)Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain. imelero@unav.es. (14)Department of Immunology and Immunotherapy, Centro de Investigación Médica Aplicada (CIMA), Universidad de Navarra, Pamplona, Spain. imelero@unav.es.

Visual Storytelling Enhances Knowledge Dissemination in Biomedical Science

Research findings in biomedical science are often summarized in statistical plots and sophisticated data presentations. Such visualizations are challenging for people who lack the appropriate scientific background or even experts who work in other areas. Scientists have to maximize knowledge dissemination by improving the communication of their findings to the public. To address the need for compelling and successful infographics in biomedical science, we propose a new theoretical framework for Visual Storytelling and illustrate its potential application through two visual stories, one on vaccine safety and one on cancer immunotherapy. In both examples, we rely on solid data and combine multiple media (photographs, illustrations, choropleth maps, tables, graphs, and charts) with text to create powerful visual stories for the selected target audiences. If fully validated, the proposed theory may shed light into non-traditional techniques for building visual stories and further the agenda of creating compelling information visualizations.

Author Info: (1) Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD. Electronic address: tbotsis1@jhmi.edu. (2) Department of Art as Applied to Medicine, Johns H

Author Info: (1) Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD. Electronic address: tbotsis1@jhmi.edu. (2) Department of Art as Applied to Medicine, Johns Hopkins University School of Medicine, Baltimore, MD. (3) Department of Health, Behavior and Society, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD. (4) Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD.

The strategic combination of trastuzumab emtansine with oncolytic rhabdoviruses leads to therapeutic synergy

We have demonstrated that microtubule destabilizing agents (MDAs) can sensitize tumors to oncolytic vesicular stomatitis virus (VSVDelta51) in various preclinical models of cancer. The clinically approved T-DM1 (Kadcyla(R)) is an antibody-drug conjugate consisting of HER2-targeting trastuzumab linked to the potent MDA and maytansine derivative DM1. We reveal that combining T-DM1 with VSVDelta51 leads to increased viral spread and tumor killing in trastuzumab-binding, VSVDelta51-resistant cancer cells. In vivo, co-treatment of VSVDelta51 and T-DM1 increased overall survival in HER2-overexpressing, but trastuzumab-refractory, JIMT1 human breast cancer xenografts compared to monotherapies. Furthermore, viral spread in cultured HER2(+) human ovarian cancer patient-derived ascites samples was enhanced by the combination of VSVDelta51 and T-DM1. Our data using the clinically approved Kadcyla(R) in combination with VSVDelta51 demonstrates proof of concept that targeted delivery of a viral-sensitizing molecule using an antibody-drug conjugate can enhance oncolytic virus activity and provides rationale for translation of this approach.

Author Info: (1) Centre for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, ON, K1H 8L6, Canada. (2) Centre for Innovative Cancer Therapeutics, Ottawa Hospital Resea

Author Info: (1) Centre for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, ON, K1H 8L6, Canada. (2) Centre for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, ON, K1H 8L6, Canada. Department of Biochemistry, Microbiology, and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, K1H 8M5, Canada. (3) Centre for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, ON, K1H 8L6, Canada. Department of Biochemistry, Microbiology, and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, K1H 8M5, Canada. (4) Centre for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, ON, K1H 8L6, Canada. (5) Centre for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, ON, K1H 8L6, Canada. (6) Centre for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, ON, K1H 8L6, Canada. (7) Centre for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, ON, K1H 8L6, Canada. Department of Biochemistry, Microbiology, and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, K1H 8M5, Canada. (8) Centre for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, ON, K1H 8L6, Canada. Department of Biochemistry, Microbiology, and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, K1H 8M5, Canada. (9) Centre for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, ON, K1H 8L6, Canada. Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, K1H 8M5, Canada. (10) Centre for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, ON, K1H 8L6, Canada. (11) Centre for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, ON, K1H 8L6, Canada. Department of Biochemistry, Microbiology, and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, K1H 8M5, Canada. (12) Centre for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, ON, K1H 8L6, Canada. Department of Biochemistry, Microbiology, and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, K1H 8M5, Canada. (13) Centre for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, ON, K1H 8L6, Canada. (14) Centre for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, ON, K1H 8L6, Canada. Department of Biochemistry, Microbiology, and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, K1H 8M5, Canada. (15) Centre for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, ON, K1H 8L6, Canada. Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, K1H 8M5, Canada. (16) Centre for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, ON, K1H 8L6, Canada. jsdiallo@ohri.ca. Department of Biochemistry, Microbiology, and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, K1H 8M5, Canada. jsdiallo@ohri.ca.

Engagement of CD45 alters early signaling events in human T cells co-stimulated through TCR + CD28

Previously our lab has shown that co-stimulation of human T cells through different co-stimulatory molecules tune differentiation to different phenotypes. An open question is where in the signaling pathways induced by the co-stimulation do differences occur that contribute to outcome of differentiation. In this project, we investigate the early signaling process by comparing events that follow engagement of CD45 alone or in association with a co-stimulatory molecule: CD28. CD45 plays a crucial role to initiate T cell signaling by dephosphorylating a negatively regulatory tyrosine residue in Src family kinases such as Lck. First, we observed that engagement of CD45 alone induced signaling in T cells. We observed that TCR/CD3 stimulation with CD45 promoted prolonged Lck association with TCR/CD3 complex and Lck remained associated during TCR/CD3 + CD28 + CD45 stimulation as well. We concluded that Lck association is dependent on TCR/CD3 and CD45 engagement. Hence, CD45 altered early signaling events in T cells.

Author Info: (1) Department of Molecular Biosciences, University of Kansas, Lawrence, KS, United States. Electronic address: a751b166@ku.edu. (2) Department of Pediatrics, Division of Allergy,

Author Info: (1) Department of Molecular Biosciences, University of Kansas, Lawrence, KS, United States. Electronic address: a751b166@ku.edu. (2) Department of Pediatrics, Division of Allergy, Asthma, and Immunology, Children's Mercy Hospital, Kansas City, MO, United States. (3) Department of Molecular Biosciences, University of Kansas, Lawrence, KS, United States.

Understanding the Differentiation, Expansion, Recruitment and Suppressive Activities of Myeloid-Derived Suppressor Cells in Cancers

There has been a great interest in myeloid-derived suppressor cells (MDSCs) due to their biological functions in tumor-mediated immune escape by suppressing antitumor immune responses. These cells arise from altered myelopoiesis in response to the tumor-derived factors. The most recognized function of MDSCs is suppressing anti-tumor immune responses by impairing T cell functions, and these cells are the most important players in cancer dissemination and metastasis. Therefore, understanding the factors and the mechanism of MDSC differentiation, expansion, and recruitment into the tumor microenvironment can lead to its control. However, most of the studies only defined MDSCs with no further characterization of granulocytic and monocytic subsets. In this review, we discuss the mechanisms by which specific MDSC subsets contribute to cancers. A better understanding of MDSC subset development and the specific molecular mechanism is needed to identify treatment targets. The understanding of the specific molecular mechanisms responsible for MDSC accumulation would enable more precise therapeutic targeting of these cells.

Author Info: (1) Centre for Virus and Vaccine Research, School of Science and Technology, Sunway University, Bandar Sunway, Kuala Lumpur, Selangor 47500, Malaysia. (2) Division of Life Sciences

Author Info: (1) Centre for Virus and Vaccine Research, School of Science and Technology, Sunway University, Bandar Sunway, Kuala Lumpur, Selangor 47500, Malaysia. (2) Division of Life Sciences, College of Life Sciences and Biotechnology, Korea University, Seoul 136-701, Korea. (3) Centre for Virus and Vaccine Research, School of Science and Technology, Sunway University, Bandar Sunway, Kuala Lumpur, Selangor 47500, Malaysia.

Macrophage targeting in cancer

Tumorigenesis is not only determined by the intrinsic properties of cancer cells but also by their interactions with components of the tumor microenvironment (TME). Tumor-associated macrophages (TAMs) are among the most abundant immune cells in the TME. During initial stages of tumor development, macrophages can either directly promote antitumor responses by killing tumor cells or indirectly recruit and activate other immune cells. As genetic changes occur within the tumor or T helper 2 (TH 2) cells begin to dominate the TME, TAMs begin to exhibit an immunosuppressive protumor phenotype that promotes tumor progression, metastasis, and resistance to therapy. Thus, targeting TAMs has emerged as a strategy for cancer therapy. To date, TAM targeting strategies have focused on macrophage depletion and inhibition of their recruitment into the TME. However, these strategies have shown limited therapeutic efficacy, although trials are still underway with combination therapies. The fact that macrophages have the potential for antitumor activity has moved the TAM targeting field toward the development of TAM-reprogramming strategies to support this antitumor immune response. Here, we discuss the various roles of TAMs in cancer therapy and their immunosuppressive properties, as well as implications for emerging checkpoint inhibitor-based immunotherapies. We review state-of-the-art TAM-targeting strategies, focusing on current ones at the preclinical and clinical trial stages that aim to reprogram TAMs as an oncological therapy.

Author Info: (1) MRC Centre for Reproductive Health, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, United Kingdom. (2) MRC Centre for Reproductive Health, Queen's

Author Info: (1) MRC Centre for Reproductive Health, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, United Kingdom. (2) MRC Centre for Reproductive Health, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, United Kingdom. (3) MRC Centre for Reproductive Health, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, United Kingdom.

High systemic and tumor-associated IL-8 correlates with reduced clinical benefit of PD-L1 blockade

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Analyzing data from various clinical trials of PD-1/PD-L1 checkpoint blockade, Yuen and Liu et al. found that IL-8 serves as an independent biomarker that predicts shorter survival and reduced clinical benefit from immunotherapy. Their data suggest that IL-8 likely recruits immunosuppressive myeloid cells like neutrophils and macrophages to tumors, resulting in tumor environments that exclude T cells and/or suppress T cell activation. 

Analyzing data from various clinical trials of PD-1/PD-L1 checkpoint blockade, Yuen and Liu et al. found that IL-8 serves as an independent biomarker that predicts shorter survival and reduced clinical benefit from immunotherapy. Their data suggest that IL-8 likely recruits immunosuppressive myeloid cells like neutrophils and macrophages to tumors, resulting in tumor environments that exclude T cells and/or suppress T cell activation. 

ABSTRACT: Although elevated plasma interleukin-8 (pIL-8) has been associated with poor outcome to immune checkpoint blockade (1), this has not been comprehensively evaluated in large randomized studies. Here we analyzed circulating pIL-8 and IL8 gene expression in peripheral blood mononuclear cells and tumors of patients treated with atezolizumab (anti-PD-L1 monoclonal antibody) from multiple randomized trials representing 1,445 patients with metastatic urothelial carcinoma (mUC) and metastatic renal cell carcinoma. High levels of IL-8 in plasma, peripheral blood mononuclear cells and tumors were associated with decreased efficacy of atezolizumab in patients with mUC and metastatic renal cell carcinoma, even in tumors that were classically CD8(+) T cell inflamed. Low baseline pIL-8 in patients with mUC was associated with increased response to atezolizumab and chemotherapy. Patients with mUC who experienced on-treatment decreases in pIL-8 exhibited improved overall survival when treated with atezolizumab but not with chemotherapy. Single-cell RNA sequencing of the immune compartment showed that IL8 is primarily expressed in circulating and intratumoral myeloid cells and that high IL8 expression is associated with downregulation of the antigen-presentation machinery. Therapies that can reverse the impacts of IL-8-mediated myeloid inflammation will be essential for improving outcomes of patients treated with immune checkpoint inhibitors.

Author Info: (1) Genentech, San Francisco, CA, USA. (2) Genentech, San Francisco, CA, USA. (3) Genentech, San Francisco, CA, USA. (4) Genentech, San Francisco, CA, USA. (5) Genentech, San Franc

Author Info: (1) Genentech, San Francisco, CA, USA. (2) Genentech, San Francisco, CA, USA. (3) Genentech, San Francisco, CA, USA. (4) Genentech, San Francisco, CA, USA. (5) Genentech, San Francisco, CA, USA. (6) Genentech, San Francisco, CA, USA. (7) Genentech, San Francisco, CA, USA. (8) Genentech, San Francisco, CA, USA. (9) Genentech, San Francisco, CA, USA. (10) Genentech, San Francisco, CA, USA. (11) Genentech, San Francisco, CA, USA. (12) Genentech, San Francisco, CA, USA. (13) Genentech, San Francisco, CA, USA. (14) Genentech, San Francisco, CA, USA. (15) Genentech, San Francisco, CA, USA. (16) Genentech, San Francisco, CA, USA. (17) Genentech, San Francisco, CA, USA. (18) Roche Products Ltd., Welwyn Garden City, UK. (19) Genentech, San Francisco, CA, USA. (20) Netherlands Cancer Institute, Amsterdam, the Netherlands. (21) Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (22) Beth Israel Deaconess Medical Center, Boston, MA, USA. (23) Barts Experimental Cancer Medicine Centre, Barts Cancer Institute, Queen Mary University of London, London, UK. (24) Genentech, San Francisco, CA, USA. (25) Genentech, San Francisco, CA, USA. huseni.mahrukh@gene.com. (26) Genentech, San Francisco, CA, USA. mariathasan.sanjeev@gene.com.

Single-cell RNA-sequencing of tumor-infiltrating NK cells reveals that inhibition of transcription factor HIF-1α unleashes NK cell activity

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Ni, Wang, and Stojanovic et al. show that HIF-1α suppresses NK cell activation and effector function and promotes tumor growth. ScRNAseq showed increased activation markers (IFNγ, NF-κB, and Iκbζ) in HIF-1α-deficient mouse NK cells, which was dependent on myeloid cells-derived IL-18. Ex-vivo treatment of human NK cells with HIF-1α inhibitor enhanced IFNγ, TNFα, and CD107a expression, and HIF-1α expression in tumor-infiltrating NK cells negatively correlated with an NK-IL18-IFNG gene signature in NSCLC patients. The NK-IL18-IFNGhigh gene signature was associated with increased OS in patients with melanoma, breast, and cervical cancer.

Contributed by Shishir Pant

Ni, Wang, and Stojanovic et al. show that HIF-1α suppresses NK cell activation and effector function and promotes tumor growth. ScRNAseq showed increased activation markers (IFNγ, NF-κB, and Iκbζ) in HIF-1α-deficient mouse NK cells, which was dependent on myeloid cells-derived IL-18. Ex-vivo treatment of human NK cells with HIF-1α inhibitor enhanced IFNγ, TNFα, and CD107a expression, and HIF-1α expression in tumor-infiltrating NK cells negatively correlated with an NK-IL18-IFNG gene signature in NSCLC patients. The NK-IL18-IFNGhigh gene signature was associated with increased OS in patients with melanoma, breast, and cervical cancer.

Contributed by Shishir Pant

ABSTRACT: Enhancing immune cell functions in tumors remains a major challenge in cancer immunotherapy. Hypoxia is a common feature of solid tumors, and cells adapt by upregulating the transcription factor HIF-1alpha. Here, we defined the transcriptional landscape of mouse tumor-infiltrating natural killer (NK) cells by using single-cell RNA sequencing. Conditional deletion of Hif1a in NK cells resulted in reduced tumor growth, elevated expression of activation markers, effector molecules, and an enriched NF-kappaB pathway in tumor-infiltrating NK cells. Interleukin-18 (IL-18) from myeloid cells was required for NF-kappaB activation and the enhanced anti-tumor activity of Hif1a(-/-) NK cells. Extended culture with an HIF-1alpha inhibitor increased human NK cell responses. Low HIF1A expression was associated with high expression of IFNG in human tumor-infiltrating NK cells, and an enriched NK-IL18-IFNG signature in solid tumors correlated with increased overall patient survival. Thus, inhibition of HIF-1alpha unleashes NK cell anti-tumor activity and could be exploited for cancer therapy.

Author Info: (1) Department of Immunobiochemistry, Mannheim Institute for Innate Immunoscience (MI3), Medical Faculty Mannheim, University of Heidelberg, 68167 Mannheim, Germany; Innate Immunit

Author Info: (1) Department of Immunobiochemistry, Mannheim Institute for Innate Immunoscience (MI3), Medical Faculty Mannheim, University of Heidelberg, 68167 Mannheim, Germany; Innate Immunity, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. (2) Division of Theoretical Systems Biology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. (3) Department of Immunobiochemistry, Mannheim Institute for Innate Immunoscience (MI3), Medical Faculty Mannheim, University of Heidelberg, 68167 Mannheim, Germany; Innate Immunity, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. (4) Division of Theoretical Systems Biology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. (5) Department of Immunobiochemistry, Mannheim Institute for Innate Immunoscience (MI3), Medical Faculty Mannheim, University of Heidelberg, 68167 Mannheim, Germany. (6) Innate Immunity, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. (7) Innate Immunity, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. (8) Department of Immunobiochemistry, Mannheim Institute for Innate Immunoscience (MI3), Medical Faculty Mannheim, University of Heidelberg, 68167 Mannheim, Germany; Innate Immunity, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. (9) Department of Dermatology, Venereology, and Allergology, University Medical Center and Medical Faculty Mannheim, University of Heidelberg, and Center of Excellence in Dermatology, 68167 Mannheim, Germany. (10) Department of Dermatology, Venereology, and Allergology, University Medical Center and Medical Faculty Mannheim, University of Heidelberg, and Center of Excellence in Dermatology, 68167 Mannheim, Germany; European Center for Angioscience (ECAS), Medical Faculty Mannheim, University of Heidelberg, 68167 Mannheim, Germany. (11) Institute of Pharmacology and Toxicology, Department for Biomedical Sciences, University of Veterinary Medicine, 1210 Vienna, Austria. (12) Division of Theoretical Systems Biology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. (13) Department of Immunobiochemistry, Mannheim Institute for Innate Immunoscience (MI3), Medical Faculty Mannheim, University of Heidelberg, 68167 Mannheim, Germany; Innate Immunity, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; European Center for Angioscience (ECAS), Medical Faculty Mannheim, University of Heidelberg, 68167 Mannheim, Germany. Electronic address: adelheid.cerwenka@medma.uni-heidelberg.de.

REVIEW: The CD47-SIRPα Immune Checkpoint

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Logtenberg et al. thoroughly review the signaling between the SIRPα receptor (found on myeloid cells) and its ligand CD47 (the “don’t eat me” signal found on many types of healthy and cancer cells). The CD47-SIRPα axis regulates tissue homeostasis and plays a role in fibrotic diseases, atherosclerosis, and cancer. While blockade of the CD47-SIRPα axis alone has been ineffective in tumors, it has significantly enhanced the antitumor response in immunotherapy combinations. A key unanswered question for targeting the CD47-SIRPα axis is understanding the dynamic and spatial balancing of inhibitory signaling with activating signals.

Contributed by Anna Scherer

Logtenberg et al. thoroughly review the signaling between the SIRPα receptor (found on myeloid cells) and its ligand CD47 (the “don’t eat me” signal found on many types of healthy and cancer cells). The CD47-SIRPα axis regulates tissue homeostasis and plays a role in fibrotic diseases, atherosclerosis, and cancer. While blockade of the CD47-SIRPα axis alone has been ineffective in tumors, it has significantly enhanced the antitumor response in immunotherapy combinations. A key unanswered question for targeting the CD47-SIRPα axis is understanding the dynamic and spatial balancing of inhibitory signaling with activating signals.

Contributed by Anna Scherer

ABSTRACT: The cytotoxic activity of myeloid cells is regulated by a balance of signals that are transmitted through inhibitory and activating receptors. The Cluster of Differentiation 47 (CD47) protein, expressed on both healthy and cancer cells, plays a pivotal role in this balance by delivering a “don’t eat me signal” upon binding to the Signal-regulatory protein alpha (SIRPα) receptor on myeloid cells. Here, we review the current understanding of the role of the CD47-SIRPα axis in physiological tissue homeostasis and as a promising therapeutic target in, among others, oncology, fibrotic diseases, atherosclerosis, and stem cell therapies. We discuss gaps in understanding and highlight where additional insight will be beneficial to allow optimal exploitation of this myeloid cell checkpoint as a target in human disease.

Author Info: (1) Division of Molecular Oncology and Immunology, Oncode Institute, the Netherlands Cancer Institute, Amsterdam, the Netherlands; (2) Department of Medical Oncology, Leiden Univer

Author Info: (1) Division of Molecular Oncology and Immunology, Oncode Institute, the Netherlands Cancer Institute, Amsterdam, the Netherlands; (2) Department of Medical Oncology, Leiden University Medical Center (LUMC), Leiden, the Netherlands ; (3) Department of Immunohematology and Bloodtransfusion, Leiden University Medical Center, Leiden, the Netherlands

Relationship between T cell receptor clonotype and PD-1 expression of tumor-infiltrating lymphocytes in colorectal cancer

Adoptive T cell therapy using tumor-specific T cells or T cell receptor (TCR)-modified T cells is a promising next-generation immunotherapy. The major source of tumor-reactive T cells is PD-1(+) tumor-infiltrating lymphocytes (TILs). In contrast, PD-1(-) TILs have received little attention. Here, we analyzed the TCRbeta repertoires of PD-1(-) and PD-1(+) CD8(+) TILs derived from colorectal cancer and breast cancer. Approximately 40 to 60% of the PD-1(+) population consisted of oligoclonal populations in both colorectal cancer and breast cancer. In contrast, approximately 37% of the PD-1(-) population consisted of an oligoclonal population in colorectal cancer, whereas 14% of them were oligoclonal in breast cancer. In colorectal cancer, the TCR repertoires of PD-1(-) CD8(+) TILs and PD-1(+) CD8(+) TILs hardly overlapped. Interestingly, clonally expanded CD8(+) TILs in primary tumors and the metastases expressing the same clonotypic TCR showed the same phenotype regarding the PD-1-expression. These results suggest that the intrinsic properties of TCRs determine the fate of TILs in terms of whether they become PD-1(+) or PD-1(-) in the tumor microenvironment. Further functional analysis of TCRs in TILs will allow us to better understand the regulatory mechanisms for PD-1 expression on TILs and may contribute to tumor immunotherapy. This article is protected by copyright. All rights reserved.

Author Info: (1) Department of Immunology, Faculty of Medicine, Academic Assembly, University of Toyama, Toyama, Japan. Department of Surgery and Science, Faculty of Medicine, Academic Assembly

Author Info: (1) Department of Immunology, Faculty of Medicine, Academic Assembly, University of Toyama, Toyama, Japan. Department of Surgery and Science, Faculty of Medicine, Academic Assembly, University of Toyama, Toyama, Japan. (2) Department of Immunology, Faculty of Medicine, Academic Assembly, University of Toyama, Toyama, Japan. (3) Department of Immunology, Faculty of Medicine, Academic Assembly, University of Toyama, Toyama, Japan. (4) Department of Immunology, Faculty of Medicine, Academic Assembly, University of Toyama, Toyama, Japan. (5) Department of Immuno-Gene Therapy, Mie University Graduate School of Medicine, Mie, Japan. (6) Department of Immuno-Gene Therapy, Mie University Graduate School of Medicine, Mie, Japan. (7) Department of Immunology, Faculty of Medicine, Academic Assembly, University of Toyama, Toyama, Japan. Department of Obstetrics and Gynecology, Faculty of Medicine, Academic Assembly, University of Toyama, Toyama, Japan. (8) Department of Immunology, Faculty of Medicine, Academic Assembly, University of Toyama, Toyama, Japan. Department of Surgery and Science, Faculty of Medicine, Academic Assembly, University of Toyama, Toyama, Japan. (9) Department of Surgery and Science, Faculty of Medicine, Academic Assembly, University of Toyama, Toyama, Japan. (10) Department of Immunology, Faculty of Medicine, Academic Assembly, University of Toyama, Toyama, Japan. (11) Department of Obstetrics and Gynecology, Faculty of Medicine, Academic Assembly, University of Toyama, Toyama, Japan. (12) Department of Surgery and Science, Faculty of Medicine, Academic Assembly, University of Toyama, Toyama, Japan. (13) Department of Immunology, Faculty of Medicine, Academic Assembly, University of Toyama, Toyama, Japan. (14) Department of Immuno-Gene Therapy, Mie University Graduate School of Medicine, Mie, Japan. (15) Department of Immunology, Faculty of Medicine, Academic Assembly, University of Toyama, Toyama, Japan.

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