TY - JOUR

T1 - The effects of targeted immune-regulatory strategies on tumor-specific T-cell responses in vitro

AU - Presti, Mario

AU - Westergaard, Marie Christine Wulff

AU - Draghi, Arianna

AU - Chamberlain, Christopher Aled

AU - Gokuldass, Aishwarya

AU - Svane, Inge Marie

AU - Donia, Marco

PY - 2021

Y1 - 2021

N2 - 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.

AB - 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.

KW - Immune checkpoint inhibitors

KW - Immune regulatory drugs

KW - Immune-related adverse events

KW - Tumor-infiltrating lymphocytes

U2 - 10.1007/s00262-020-02760-z

DO - 10.1007/s00262-020-02760-z

M3 - Journal article

C2 - 33165629

AN - SCOPUS:85095687678

VL - 70

SP - 1771

EP - 1776

JO - Cancer Immunology, Immunotherapy

JF - Cancer Immunology, Immunotherapy

SN - 0340-7004

ER -