T-cells of invasive candidiasis patients show patterns of T-cell-exhaustion suggesting checkpoint blockade as treatment option - 14/02/22

Doi : 10.1016/j.jinf.2021.12.009

Sibylle C. Mellinghoff ^a,^b,^c,^{^{1
These authors contributed equally to this work.},}^⁎ , Martin Thelen ^d,^{^{1
These authors contributed equally to this work.}}, Christiane Bruns ^e, Maria Garcia-Marquez ^d, Pia Hartmann ^f,^g, Tatjana Lammertz ^a, Jonas Lehmann ^d, Angela Nowag ^f,^g, Jannik Stemler ^a,^b,^c, Kerstin Wennhold ^d, Oliver A. Cornely ^a,^b,^c,^h, Michael S. von Bergwelt-Baildon ^i,^j,^k, Hans A. Schlößer ^d,^e
^a Department I of Internal Medicine, Excellence Centre for Medical Mycology (ECMM), University of Cologne, Faculty of Medicine and University Hospital Cologne, Kerpener Str. 62, Cologne 50937, Germany
^b Translational Research, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany
^c Partner Site Bonn-Cologne, German Centre for Infection Research (DZIF), Cologne, Germany
^d Centre for Molecular Medicine Cologne, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany
^e Department of General, Visceral, Cancer and Transplantation Surgery, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany
^f Wisplinghoff Laboratories, Cologne, Germany
^g Immunology and Hygiene (IMMIH), University of Cologne Institute for Medical Microbiology, Cologne, Germany
^h Clinical Trials Centre Cologne, ZKS Köln, Cologne, Germany
ⁱ Department of Medicine III, University Hospital, Ludwig Maximilian University Munich, Munich, Germany
^j Laboratory for Translational Cancer Immunology, Gene Centre, Ludwig Maximilian University Munich, Munich, Germany
^k German Cancer Consortium (DKTK), Partner site Munich, Munich, Germany

^⁎Corresponding author: Department I of Internal Medicine, Excellence Centre for Medical Mycology (ECMM), University of Cologne, Faculty of Medicine and University Hospital Cologne, Kerpener Str. 62, Cologne 50937, Germany.Department I of Internal Medicine, Excellence Centre for Medical Mycology (ECMM)University of Cologne, Faculty of Medicine and University Hospital CologneKerpener Str. 62Cologne50937Germany

Summary

Objective

Recent data imply that strengthening host immunity by checkpoint inhibition improves outcome in invasive fungal infections (IFI), particularly in candidiasis.

Methods

To assess T-cell exhaustion in this context, we compared peripheral blood mononuclear cells (PBMCs) and serum samples of patients with invasive Candida albicans infection (IC, n = 21) to PBMCs or tumor-infiltrating lymphocytes (TILs) from cancer patients (n = 14) and PBMCs of healthy controls (n = 20). Type and differentiation of lymphocytes and expression of 29 immune-regulatory molecules were analyzed by flow cytometry. C. albicans specific responses were assessed by FluoroSpot (n = 8) and antibody measurement (n = 14).

Results

Fractions and phenotypes of lymphocyte subsets in PBMCs of IC patients were similar compared to PBMCs of controls, while they were different in TILs. PBMCs of patients with IC showed increased expression of immune-checkpoint molecules. The pattern of upregulated molecules was similar to TILs, but not present in PBMCs of control cancer patients. Fractions of T-cells expressing PD-1 and TIGIT were higher in IC patients that died. FluoroSpot analysis showed a Candida-specific IFN-y or IL-2 response in 5/8 patients, enhanced by addition of nivolumab in vitro.

Conclusions

Together with preclinical data and preliminary evidence of clinical efficacy in mucormycosis, our results support clinical evaluation of immune-checkpoint inhibition in IFI treatment.

Trial registration

NCT04533087; retrospectively registered on August 31, 2020

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Keywords : Invasive fungal Infection, Candidiasis, Fungal sepsis, Immunotherapy, Immune checkpoint inhibition, T-cell exhaustion

Plan

Introduction

Materials and methods

Study design and setting

Patients and samples

Data assessment

Preparation of PBMCs and TILs

Flow cytometric phenotyping of lymphocytes

FluoroSpot assay

Qualitative detection of antibodies

Statistical analyses and visualization

Results

Patient characteristics

Lymphocyte subsets in PBMCs are similar while phenotypes differ between patients with invasive Candida infection and solid tumors

PBMCs of patients with invasive candidiasis show increased expression of immune-checkpoint molecules, which parallels tumor-infiltrating lymphocytes

Candida-specific antibodies

PD-1 and TIGIT expression on T-cells correlates with patient mortality and anti-PD-1 immune-checkpoint blockade can enhance a C. albicans specific immune response

Discussion

Conclusions

Funding and role of the funding source

Availability of data and material

Code availability

Authors’ contributions

Ethics approval

Consent to participate

Consent to publish

Supplementary meterial

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Vol 84 - N° 2

P. 237-247 - février 2022 Retour au numéro

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T-cells of invasive candidiasis patients show patterns of T-cell-exhaustion suggesting checkpoint blockade as treatment option - 14/02/22

Summary

Objective

Methods

Results

Conclusions

Trial registration

Plan

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