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Increased indoleamine 2,3-dioxygenase activity and expression in prostate cancer following targeted immunotherapy

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Abstract

Background

We previously found that PD-L1 expression is increased on tumor cells following vaccination treatments that lead to increased tumor-specific T cells that secrete IFNγ. Indoleamine 2,3-dioxygenase (IDO) is another IFNγ inducible gene that has potent immunosuppressive effects. There have been reports of IDO expression in prostate cancer; however, it is unknown whether IDO expression might similarly increase in prostate tumors following T-cell-based immunotherapy.

Methods

Blood samples from normal male blood donors (n = 12) and patients with different stages of prostate cancer (n = 89), including patients with metastatic, castration-resistant prostate cancer treated with a DNA vaccine and/or pembrolizumab, were evaluated for IDO activity by kynurenine and tryptophan levels. Metastatic tissue biopsies obtained pre- and post-treatments were evaluated for IDO expression. IDO suppression of vaccine-induced T-cell function was assessed by ELISPOT.

Results

Overall, IDO activity was increased in patients with more advanced prostate cancer. This activity, and IDO expression as detected immunohistochemically, increased following treatment with either a DNA vaccine encoding the prostatic acid phosphatase (PAP) tumor antigen or PD-1 blockade with pembrolizumab. Increased IDO activity after treatment was associated with the absence of clinical effect, as assessed by lack of PSA decline following treatment. Increased antigen-specific T-cell response, as measured by IFNγ release, to the vaccine target antigen was detected following in vitro stimulation of peripheral blood cells with 1-methyltryptophan.

Conclusions

These findings suggest that IDO expression is a mechanism of immune evasion used by prostate cancer and that future clinical trials using T-cell-based immune strategies might best include IDO inhibition.

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Abbreviations

1-MT:

1-methyltryptophan

CTLA-4:

Cytolytic T-lymphocyte antigen 4

DAPI:

4′,6-diamidino-2-phenylindole

DNA:

Deoxyribonucleic acid

ELISA:

Enzyme-linked immunosorbent assay

ELISPOT:

Enzyme-linked immunosorbent spot assay

FFPE:

Formalin-fixed paraffin-embedded

IDO:

Indoleamine 2,3-dioxygenase

IF:

Immunofluorescent

IFNγ:

Interferon-gamma

IHC:

Immunohistochemistry

IRB:

Institutional review board

Kyn:

Kynurenine

LC/MS:

Liquid chromatography/mass spectrometry

mCRPC:

Metastatic, castration-resistant prostate cancer

MDSC:

Myeloid-derived suppressor cell

PAP:

Prostatic acid phosphatase

PBMC:

Peripheral blood mononuclear cells

PD-(L)1:

Programmed death-1 (ligand)

PSA:

Prostate-specific antigen

PSMA:

Prostate-specific membrane antigen

pTVG-HP:

DNA vaccine-encoding human prostatic acid phosphatase

TIL:

Tumor-infiltrating lymphocyte

TRAMP:

Transgenic adenocarcinoma of mouse prostate

trp:

Tryptophan

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Acknowledgements

We are grateful to Dr. Robert Newton (Incyte) and Worldwide Clinical Trials for conducting analysis of tryptophan and kynurenine concentrations in blood samples, and to Dr. Glenn Liu for helpful comments on the manuscript.

Funding

This work was supported by the Prostate Cancer Foundation (2014 Movember-PCF Challenge Award) and by National Institutes of Health R01 CA219154 and P30 CA014520.

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Authors and Affiliations

  1. 7007 Wisconsin Institutes for Medical Research, University of Wisconsin Carbone Cancer Center, 1111 Highland Avenue, Madison, WI, 53705, USA

    Chris D. Zahm, Laura E. Johnson & Douglas G. McNeel

Authors
  1. Chris D. Zahm
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  2. Laura E. Johnson
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  3. Douglas G. McNeel
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Contributions

CDZ conducted and analyzed laboratory studies described; DGM designed the study and oversaw analysis; all authors contributed to the writing and approval of the final manuscript.

Corresponding author

Correspondence to Douglas G. McNeel.

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Conflict of interest

Douglas G. McNeel has ownership interest, has received research support, and serves as consultant to Madison Vaccines, Inc. which has licensed intellectual property related to this content. None of the other authors have relevant potential conflicts of interest.

Ethical approval

Long-term use of blood samples collected from research subjects who had previously consented for remaining samples to be used for immunology-related research was approved on 11/21/2016 under University of Wisconsin IRB protocol 2013-0126-CR004 as a minimal risk protocol, not requiring additional patient consent.

Informed consent

Samples were collected under University of Wisconsin IRB-approved protocols, and all patients gave written, informed consent for remaining samples to be used for research.

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Zahm, C.D., Johnson, L.E. & McNeel, D.G. Increased indoleamine 2,3-dioxygenase activity and expression in prostate cancer following targeted immunotherapy. Cancer Immunol Immunother 68, 1661–1669 (2019). https://doi.org/10.1007/s00262-019-02394-w

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