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Novel strategies for inhibiting PD-1 pathway-mediated immune suppression while simultaneously delivering activating signals to tumor-reactive T cells

  • Focussed Research Review
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Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

We previously developed cell-based vaccines as therapeutics for metastatic cancers. The vaccines were aimed at activating type I CD4+T cells and consisted of tumor cells transfected with genes encoding syngeneic MHC class II and CD80 costimulatory molecules, and lacking the MHC II-associated invariant chain. The vaccines showed some efficacy in mice with sarcoma, melanoma, and breast cancer and activated MHC class II syngeneic T cells from breast, lung, and melanoma patients. During the course of the vaccine studies, we observed that CD80 not only costimulated naïve T cells, but also bound to PD-L1 and prevented tumor cell-expressed PD-L1 from binding to its receptor PD-1 on activated T cells. A soluble form of CD80 (CD80-Fc) had the same effect and sustained IFNγ production by both human and murine PD-1+ activated T cells in the presence of PD-L1+ human or mouse tumor cells, respectively. In vitro studies with human tumor cells indicated that CD80-Fc was more effective than antibodies to either PD-1 or PD-L1 in sustaining T cell production of IFNγ. Additionally, in vivo studies with a murine tumor demonstrated that CD80-Fc was more effective than antibodies to PD-L1 in extending survival time. Studies with human T cells blocked for CD28 and with T cells from CD28 knockout mice demonstrated that CD80-Fc simultaneously inhibited PD-L1/PD-1-mediated immune suppression and delivered costimulatory signals to activated T cells, thereby amplifying T cell activation. These results suggest that CD80-Fc may be a useful monotherapy that minimizes PD-1 pathway immune suppression while simultaneously activating tumor-reactive T cells.

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Abbreviations

APC:

Antigen-presenting cell

CD80-Fc:

Soluble CD80 (two extracellular domains of CD80 fused to the Fc domain of Ig)

CTLA-4:

Cytotoxic T lymphocyte antigen 4

DC:

Dendritic cells

IgC:

Immunoglobulin-like constant region

IgV:

Immunoglobulin-like variable region

mAbs:

Monoclonal antibodies

PD-1:

Programmed death 1

PD-L1:

Programmed death ligand 1

PBMC:

Peripheral blood mononuclear cells

PHA:

Phytohemagglutinin

TcR:

T cell receptor for antigen

TIL:

Tumor-infiltrating T cells

TROY-Fc:

Toxicity and JNK inducer or TNFRSF19 protein fused to the Fc domain of Ig

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Acknowledgments

This work was supported by grants from the U.S. National Institutes of Health (RO1CA84232) and the State of Maryland Technology Development Corp. (TEDCO; 1000308). The authors thank Ms. Virginia Clements for her excellent technical support and Dr. Robert C. Rosenberg for the structural analyses of Fig. 2.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Biological Sciences, University of Maryland Baltimore County, 1000 Hilltop Circle, Baltimore, MD, 21250, USA

    Suzanne Ostrand-Rosenberg, Lucas A. Horn & Juan A. Alvarez

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  1. Suzanne Ostrand-Rosenberg
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  2. Lucas A. Horn
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  3. Juan A. Alvarez
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Correspondence to Suzanne Ostrand-Rosenberg.

Additional information

This paper is a Focussed Research Review based on a presentation given at the Fourteenth International Conference on Progress in Vaccination against Cancer (PIVAC 14), held in Rome, Italy, 24th–26th September, 2014. It is part of a Cancer Immunology, Immunotherapy series of Focussed Research Reviews and meeting report.

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Ostrand-Rosenberg, S., Horn, L.A. & Alvarez, J.A. Novel strategies for inhibiting PD-1 pathway-mediated immune suppression while simultaneously delivering activating signals to tumor-reactive T cells. Cancer Immunol Immunother 64, 1287–1293 (2015). https://doi.org/10.1007/s00262-015-1677-5

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