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The effects of targeted immune-regulatory strategies on tumor-specific T-cell responses in vitro

Abstract

Background

Immune-related adverse events (IrAEs) are auto-immune reactions associated with immune checkpoint inhibitor-based therapy (ICI). Steroids are currently the first-line option for irAE management; however, recent studies have raised concerns regarding their potential impairment of tumor-specific immune responses. In this study, we investigated the in vitro effects of commonly used irAE treatment drugs on the anti-tumor activity of tumor-infiltrating lymphocytes (TILs).

Methods

Impairment of anti-tumor immune responses by four drugs (antibodies: vedolizumab and tocilizumab; small molecules: mycophenolate mofetil and tacrolimus) reported to be effective in treating irAEs was tested at clinically relevant doses in vitro and compared to a standard moderate dose of corticosteroids (small molecules) or infliximab (antibodies). TIL responses against autologous tumor cell lines, in the presence or absence of irAE drugs, were determined by flow cytometry (short-term tumor-specific T-cell activation) or xCELLigence (T-cell-mediated tumor killing).

Results

None of the tested antibodies influenced T-cell activation or T-cell-mediated tumor killing. Low-dose mycophenolate and tacrolimus did not influence T-cell activation, whereas higher doses of tacrolimus (> 1 ng/ml) impaired T-cell activation comparably to dexamethasone. All tested small molecules impaired T-cell-mediated tumor killing, with high-dose tacrolimus reducing killing at levels comparable to dexamethasone-mediated inhibition. In addition, mycophenolate and tacrolimus alone also demonstrated anti-proliferative effects on tumor cells.

Conclusions

These data support clinical testing of targeted immune-regulatory strategies in the initial phase of irAE management, as a potential replacement for corticosteroids.

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Abbreviations

ICI:

Immune checkpoint inhibitors

IrAE:

Immune-related adverse events

TILs:

Tumor-infiltrating lymphocytes

TIRS:

Targeted immune-regulatory strategies

TME:

Tumor microenvironment

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Acknowledgements

The authors wish to thank all the patients who donated the samples used and the funding sources who generously supported this research (Danish Cancer Society R184-A11806, Sundhedsstyrelsen “Empowering Cancer Immunotherapy in Denmark”). Dr. Morten Hansen and Dr. Michael Douglas Crowther are acknowledged for technical assistance with the flow cytometry setup. Kasper Mølgaard Jensen is acknowledged for assistance in performing mycoplasma testing.

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Correspondence to Marco Donia.

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Conflict of interest

Marco Donia has received honoraria for lectures from Roche and Novartis (past 2 years); Inge Marie Svane has received honoraria for consultancies and lectures from Novartis, Roche, Merck, and Bristol-Myers Squibb; a restricted research grant from Novartis; and financial support for attending symposia from Bristol-Myers Squibb, Merck, Novartis, Pfizer, and Roche. All other authors declare that they have no conflict of interest.

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Presti, M., Westergaard, M.C.W., Draghi, A. et al. The effects of targeted immune-regulatory strategies on tumor-specific T-cell responses in vitro. Cancer Immunol Immunother 70, 1771–1776 (2021). https://doi.org/10.1007/s00262-020-02760-z

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Keywords

  • Immune-related adverse events
  • Immune checkpoint inhibitors
  • Immune regulatory drugs
  • Tumor-infiltrating lymphocytes