VISTA: an immune regulatory protein checking tumor and immune cells in cancer immunotherapy

Author(s): Xing Huang ¹ ^, ² ^, ³ ^, , Xiaozhen Zhang ¹ ^, ² ^, ³ , Enliang Li ¹ ^, ² ^, ³ , Gang Zhang ¹ ^, ² ^, ³ , Xun Wang ¹ ^, ² ^, ³ , Tianyu Tang ¹ ^, ² ^, ³ , Xueli Bai ¹ ^, ² ^, ³ ^, , Tingbo Liang ¹ ^, ² ^, ³ ^,

Publication date (Electronic): 29 June 2020

Journal: Journal of Hematology & Oncology

Publisher: BioMed Central

Keywords: Cancer immunotherapy, Co-inhibition, Co-stimulation, Immune checkpoint, VISTA

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Abstract

VISTA (V-domain immunoglobulin suppressor of T cell activation) is a well-established immune regulatory receptor. However, pre-clinical investigations indicated more complicated influences of VISTA on cancer immunity than previously recognized. Here, we review the current knowledge on the therapeutic phenotypes and molecular mechanisms that underlie the contradictory roles of VISTA in checking anti-cancer immune responses. Furthermore, we highlight the potential indeterminacy of VISTA-targeted strategies in cancer immunotherapy, with in silico analyses. In fact, VISTA functions like a homeostatic regulator that actively normalizes immune responses. Thus, the regulatory role of VISTA in anti-cancer immunity remains to be fully elucidated.

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Most cited references 22

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Hypoxia in cancer: significance and impact on clinical outcome.

Peter Vaupel, Arnulf Mayer (2007)

Hypoxia, a characteristic feature of locally advanced solid tumors, has emerged as a pivotal factor of the tumor (patho-)physiome since it can promote tumor progression and resistance to therapy. Hypoxia represents a "Janus face" in tumor biology because (a) it is associated with restrained proliferation, differentiation, necrosis or apoptosis, and (b) it can also lead to the development of an aggressive phenotype. Independent of standard prognostic factors, such as tumor stage and nodal status, hypoxia has been suggested as an adverse prognostic factor for patient outcome. Studies of tumor hypoxia involving the direct assessment of the oxygenation status have suggested worse disease-free survival for patients with hypoxic cervical cancers or soft tissue sarcomas. In head & neck cancers the studies suggest that hypoxia is prognostic for survival and local control. Technical limitations of the direct O(2) sensing technique have prompted the use of surrogate markers for tumor hypoxia, such as hypoxia-related endogenous proteins (e.g., HIF-1alpha, GLUT-1, CA IX) or exogenous bioreductive drugs. In many - albeit not in all - studies endogenous markers showed prognostic significance for patient outcome. The prognostic relevance of exogenous markers, however, appears to be limited. Noninvasive assessment of hypoxia using imaging techniques can be achieved with PET or SPECT detection of radiolabeled tracers or with MRI techniques (e.g., BOLD). Clinical experience with these methods regarding patient prognosis is so far only limited. In the clinical studies performed up until now, the lack of standardized treatment protocols, inconsistencies of the endpoints characterizing the oxygenation status and methodological differences (e.g., different immunohistochemical staining procedures) may compromise the power of the prognostic parameter used.

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SnapShot: TCGA-Analyzed Tumors.

Amy Blum, Peggy Wang, Jean C Zenklusen (2018)

This SnapShot provides a list of the tumor types characterized by The Cancer Genome Atlas (TCGA) program. Key findings shown are the most relevant discoveries described in each marker paper for the tumor type.

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Negative immune checkpoint regulation by VISTA: a mechanism of acquired resistance to anti-PD-1 therapy in metastatic melanoma patients

John F Thompson, Robyn P M Saw, Matteo Carlino … (2017)

Understanding the mechanisms of acquired resistance to anti-PD-1 will allow development of better treatment strategies for cancer patients. This study evaluated potential mechanisms of acquired resistance to anti-PD-1 in longitudinally collected metastatic melanoma patient biopsies. Thirty-four metastatic melanoma biopsies were collected from 16 patients who had initially responded to either anti-PD-1 (n=13) alone or combination of anti-PD-1 and ipilimumab (n=3) and then progressed. Biopsies were taken prior to treatment (PRE, n=12) and following progression of disease (PROG, n=22). Immunohistochemistry was performed on all biopsies to detect CD8, FOXP3, PD-1 and VISTA expression on T-cells and PTEN, β-catenin, PD-L1, HLA-A, and HLA-DPB1 expression in the tumor. The majority of patients showed significantly increased density of VISTA+ lymphocytes from PRE to PROG (12/18) (P=0.009) and increased expression of tumor PD-L1 from PRE to PROG (11/18). Intratumoral expression of FOXP3+ lymphocytes significantly increased (P=0.018) from PRE to PROG (10/18). Loss of tumor PTEN and downregulation of tumor HLA-A from PRE to PROG were each identified in 5/18 and 4/18 PROG biopsies, respectively. Downregulation of HLA-DPB1 from PRE to PROG was present in 3/18 PROG biopsies, whereas nuclear β-catenin activation was only identified in 2/18 PROG biopsies. Negative immune checkpoint regulation by VISTA represents an important potential mechanism of acquired resistance in melanoma patients treated with anti-PD-1. Downregulation of HLA-associated antigen presentation also occurs with acquired resistance. Augmentation of the VISTA immune checkpoint pathway may hold promise as a therapeutic strategy in metastatic melanoma patients, particularly those failing anti-PD-1 therapy, and warrants assessment in clinical trials.

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Author and article information

Contributors

Xing Huang:

ORCID: https://orcid.org/0000-0002-8886-2777

huangxing66@zju.edu.cn

Xueli Bai: shirleybai@zju.edu.cn

Tingbo Liang: liangtingbo@zju.edu.cn

Journal

Journal ID (nlm-ta): J Hematol Oncol

Journal ID (iso-abbrev): J Hematol Oncol

Title: Journal of Hematology & Oncology

Publisher: BioMed Central (London )

ISSN (Electronic): 1756-8722

Publication date (Electronic): 29 June 2020

Publication date PMC-release: 29 June 2020

Publication date Collection: 2020

Volume: 13

Electronic Location Identifier: 83

Affiliations

[1 ]GRID grid.13402.34, ISNI 0000 0004 1759 700X, Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, School of Medicine, , Zhejiang University, ; 79 Qingchun Road, Hangzhou, 310003 Zhejiang China

[2 ]GRID grid.13402.34, ISNI 0000 0004 1759 700X, Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, School of Medicine, , Zhejiang University, ; Hangzhou, 310003 Zhejiang China

[3 ]Innovation Center for the Study of Pancreatic Diseases of Zhejiang Province, Hangzhou, 310003 Zhejiang China

Author information

Xing Huang https://orcid.org/0000-0002-8886-2777

Article

Publisher ID: 917

DOI: 10.1186/s13045-020-00917-y

PMC ID: 7325042

PubMed ID: 32600443

SO-VID: b6f3a88e-bbc4-457f-a069-f119003b8241

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Open AccessThis 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 licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence 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 licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 9 April 2020

Date accepted : 16 June 2020

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;

Award ID: 31970696

Award ID: 81502975

Award Recipient : Xing Huang

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ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: cancer immunotherapy,co-inhibition,co-stimulation,immune checkpoint,vista

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ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: cancer immunotherapy, co-inhibition, co-stimulation, immune checkpoint, vista

VISTA: an immune regulatory protein checking tumor and immune cells in cancer immunotherapy

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Cancer Immunotherapy

Most cited references 22

Hypoxia in cancer: significance and impact on clinical outcome.

SnapShot: TCGA-Analyzed Tumors.

Negative immune checkpoint regulation by VISTA: a mechanism of acquired resistance to anti-PD-1 therapy in metastatic melanoma patients

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