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      Engineering strategies to enhance oncolytic viruses in cancer immunotherapy

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          Abstract

          Oncolytic viruses (OVs) are emerging as potentially useful platforms in treatment methods for patients with tumors. They preferentially target and kill tumor cells, leaving healthy cells unharmed. In addition to direct oncolysis, the essential and attractive aspect of oncolytic virotherapy is based on the intrinsic induction of both innate and adaptive immune responses. To further augment this efficacious response, OVs have been genetically engineered to express immune regulators that enhance or restore antitumor immunity. Recently, combinations of OVs with other immunotherapies, such as immune checkpoint inhibitors (ICIs), chimeric antigen receptors (CARs), antigen-specific T-cell receptors (TCRs) and autologous tumor-infiltrating lymphocytes (TILs), have led to promising progress in cancer treatment. This review summarizes the intrinsic mechanisms of OVs, describes the optimization strategies for using armed OVs to enhance the effects of antitumor immunity and highlights rational combinations of OVs with other immunotherapies in recent preclinical and clinical studies.

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          TGF-β attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells

          Sanjeev Mariathasan, Shannon Turley, Dorothee Nickles … (2018)
          Therapeutic antibodies that block the programmed death-ligand 1 (PD-L1)/programmed death-1 (PD-1) pathway can induce robust and durable responses in patients with various cancers, including metastatic urothelial cancer (mUC) 1–5 . However, these responses only occur in a subset of patients. Elucidating the determinants of response and resistance is key to improving outcomes and developing new treatment strategies. Here, we examined tumours from a large cohort of mUC patients treated with an anti–PD-L1 agent (atezolizumab) and identified major determinants of clinical outcome. Response was associated with CD8+ T-effector cell phenotype and, to an even greater extent, high neoantigen or tumour mutation burden (TMB). Lack of response was associated with a signature of transforming growth factor β (TGF-β) signalling in fibroblasts, particularly in patients with CD8+ T cells that were excluded from the tumour parenchyma and instead found in the fibroblast- and collagen-rich peritumoural stroma—a common phenotype among patients with mUC. Using a mouse model that recapitulates this immune excluded phenotype, we found that therapeutic administration of a TGF-β blocking antibody together with anti–PD-L1 reduced TGF-β signalling in stromal cells, facilitated T cell penetration into the centre of the tumour, and provoked vigorous anti-tumour immunity and tumour regression. Integration of these three independent biological features provides the best basis for understanding outcome in this setting and suggests that TGF-β shapes the tumour microenvironment to restrain anti-tumour immunity by restricting T cell infiltration.
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            Understanding the tumor immune microenvironment (TIME) for effective therapy

            Weiping Zou, T. Kevin Howcroft, Elisa C Woodhouse … (2018)
            The clinical successes in immunotherapy have been both astounding and at the same time unsatisfactory. Countless patients with varied tumor types have seen pronounced clinical response with immunotherapeutic intervention; however, many more patients have experienced minimal or no clinical benefit when provided the same treatment. As technology has advanced, so has the understanding of the complexity and diversity of the immune context of the tumor microenvironment and its influence on response to therapy. It has been possible to identify different subclasses of immune environment that have an influence on tumor initiation and response and therapy; by parsing the unique classes and subclasses of tumor immune microenvironment (TIME) that exist within a patient’s tumor, the ability to predict and guide immunotherapeutic responsiveness will improve, and new therapeutic targets will be revealed.
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              Primary, Adaptive, and Acquired Resistance to Cancer Immunotherapy.

              Padmanee Sharma, Siwen Hu-Lieskovan, Jennifer A. Wargo … (2017)
              Cancer immunotherapy can induce long lasting responses in patients with metastatic cancers of a wide range of histologies. Broadening the clinical applicability of these treatments requires an improved understanding of the mechanisms limiting cancer immunotherapy. The interactions between the immune system and cancer cells are continuous, dynamic, and evolving from the initial establishment of a cancer cell to the development of metastatic disease, which is dependent on immune evasion. As the molecular mechanisms of resistance to immunotherapy are elucidated, actionable strategies to prevent or treat them may be derived to improve clinical outcomes for patients.
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                Author and article information

                Contributors
                Li Yang: yl.tracy73@gmail.com
                Journal
                Journal ID (nlm-ta): Signal Transduct Target Ther
                Journal ID (iso-abbrev): Signal Transduct Target Ther
                Title: Signal Transduction and Targeted Therapy
                Publisher: Nature Publishing Group UK (London )
                ISSN (Print): 2095-9907
                ISSN (Electronic): 2059-3635
                Publication date (Electronic): 6 April 2022
                Publication date PMC-release: 6 April 2022
                Publication date Collection: 2022
                Volume: 7
                Electronic Location Identifier: 117
                Affiliations
                [1 ]GRID grid.13291.38, ISNI 0000 0001 0807 1581, State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, , Sichuan University, ; No. 17, Section 3, South Renmin Road, 610041 Chengdu, Sichuan People’s Republic of China
                [2 ]GRID grid.412605.4, ISNI 0000 0004 1798 1351, College of Bioengineering, , Sichuan University of Science & Engineering, ; No. 519, Huixing Road, 643000 Zigong, Sichuan People’s Republic of China
                Article
                Publisher ID: 951
                DOI: 10.1038/s41392-022-00951-x
                PMC ID: 8987060
                PubMed ID: 35387984
                SO-VID: 4c7f3789-0f93-4ca5-bdd2-ef7662ee8b84
                Copyright © © The Author(s) 2022
                License:

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                Date received : 3 November 2021
                Date revision received : 1 March 2022
                Date accepted : 2 March 2022
                Funding
                Funded by: FundRef https://doi.org/10.13039/501100001809, National Natural Science Foundation of China (National Science Foundation of China);
                Award ID: 82073366
                Award Recipient :
                Funded by: National Major Scientific and Technological Special Project for “Significant New Drugs Development” under grant No. 2018ZX09201018-013
                Funded by: Talents project of Sichuan University of Science & Engineering under grant number E10402637
                Categories
                Subject: Review Article
                Custom metadata
                issue-copyright-statement © The Author(s) 2022

                Keywords: cancer therapy,tumour immunology
                Data availability:
                Keywords: cancer therapy, tumour immunology

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