Protective Activity of Programmed Cell Death Protein 1 Blockade and Synergy With Caspofungin in a Murine Invasive Pulmonary Aspergillosis Model

Wurster, Sebastian; Robinson, Prema; Albert, Nathaniel D.; Tarrand, Jeffrey J.; Goff, Marisa; Swamydas, Muthulekha; Lim, Jean K.; Lionakis, Michail S.; Kontoyiannis, Dimitrios P.

doi:10.1093/infdis/jiaa264

Cited by 25 publications

(35 citation statements)

References 15 publications

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“…Eight-week-old female BALB/cAnNCrl inbred mice (Charles River Laboratories, weight 20-22 g) were immunosuppressed with 3 intraperitoneal injections of cyclophosphamide (Sigma-Aldrich, 150 mg/kg body weight on days -4 and -1, 100 mg/kg on day +3) and a subcutaneous injection of cortisone acetate (Sigma-Aldrich, 300 mg/kg on day -1), as previously described (16,20). Mice were then infected intranasally with 50,000 spores of R. arrhizus, the most common causative species of IPM in cancer patients (2).…”

Section: Murine Infection Model and Treatmentsmentioning

confidence: 99%

“…Pathogenic molds were shown to induce checkpoint pathways that can drive immune exhaustion and impair fungal clearance (13,14). Consequently, several invivo studies and clinical case reports suggested a potential of ICIs, especially agents blocking the Programmed Cell Death Protein 1 (PD-1) pathway, as an adjunct treatment for invasive mold infections (14)(15)(16)(17)(18). However, no systematic preclinical studies exist regarding the impact of ICIs on the immunopathology and outcomes of IM.…”

Section: Introductionmentioning

confidence: 99%

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Blockade of the PD-1/PD-L1 Immune Checkpoint Pathway Improves Infection Outcomes and Enhances Fungicidal Host Defense in a Murine Model of Invasive Pulmonary Mucormycosis

et al. 2022

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Anecdotal clinical reports suggested a benefit of adjunct immune checkpoint inhibitors (ICIs) to treat invasive mucormycosis. However, proof-of-concept data in animal models and mechanistic insights into the effects of ICIs on host defense against Mucorales are lacking. Therefore, we studied the effects of PD-1 and PD-L1 inhibitors (4 doses of 250 µg/kg) on outcomes and immunopathology of invasive pulmonary mucormycosis (IPM) in cyclophosphamide- and cortisone acetate-immunosuppressed mice. Rhizopus arrhizus-infected mice receiving either of the ICI treatments had significantly improved survival, less morbidity, and lower fungal burden compared to isotype-treated infected mice. While early improvement of morbidity/mortality was comparable between the ICI treatments, anti-PD-L1 provided more consistent sustained protection through day 7 post-infection than anti-PD-1. Both ICIs enhanced the fungicidal activity of ex-vivo splenocytes and effectively counteracted T-cell exhaustion; however, macrophages of ICI-treated mice showed compensatory upregulation of other checkpoint markers. Anti-PD-1 elicited stronger pulmonary release of proinflammatory cytokines and chemokines than anti-PD-L1, but also induced cytokines associated with potentially unfavorable type 2 T-helper-cell and regulatory T-cell responses. Although no signs of hyperinflammatory toxicity were observed, mice with IPM receiving ICIs, particularly anti-PD-1, had elevated serum levels of IL-6, a cytokine linked to ICI toxicities. Altogether, inhibition of the PD-1/PD-L1 pathway improved clinical outcomes of IPM in immunosuppressed mice, even without concomitant antifungals. PD-L1 inhibition yielded more favorable immune responses and more consistent protection from IPM-associated morbidity and mortality than PD-1 blockade. Future dose-effect studies are needed to define the “sweet spot” between ICI-induced augmentation of antifungal immunity and potential immunotoxicities.

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Section: Murine Infection Model and Treatmentsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Blockade of the PD-1/PD-L1 Immune Checkpoint Pathway Improves Infection Outcomes and Enhances Fungicidal Host Defense in a Murine Model of Invasive Pulmonary Mucormycosis

et al. 2022

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“…Moreover, immune checkpoint inhibitor therapy is acquiring more attention to infectious diseases [ 38 ]. Indeed, Wurster et al firstly reported that blockade of the PD-1 in vivo (animal model) would contribute to a survival advantage and accelerate Aspergillus fumigatus clearance in lung [ 39 ]. Also, an in vitro study revealed that target PD-L1 would promote a protective immunity to Aspergillus fumigatus [ 40 ].…”

Section: Resultsmentioning

confidence: 99%

Single-cell immune checkpoint landscape of PBMCs stimulated with Candida albicans

Deng

Liang

et al. 2021

Emerging Microbes & Infections

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Immune checkpoints play various important roles in tumor immunity, which usually contribute to T cells' exhaustion, leading to immunosuppression in the tumor microenvironment. However, the roles of immune checkpoints in infectious diseases, especially fungal infection, remain elusive. Here, we reanalyzed a recent published single-cell RNA-sequencing (scRNA-seq) data of peripheral blood mononuclear cells (PBMCs) stimulated with Candida albicans (C. albicans), to explore the expression patterns of immune checkpoints after C. albicans bloodstream infection. We characterized the heterogeneous pathway activities among different immune cell subpopulations after C. albicans infection. The CTLA-4 pathway was up-regulated in stimulated CD4 + and CD8 + T cells, while the PD-1 pathway showed high activity in stimulated plasmacytoid dendritic cell (pDC) and monocytes. Importantly, we found that immunosuppressive checkpoints HAVCR2 and LAG3 were only expressed in stimulated NK and CD8 + T cells, respectively. Their viabilities were validated by flow cytometry. We also identified three overexpressed genes (ISG20, LY6E, ISG15) across all stimulated cells. Also, two monocyte-specific overexpressed genes (SNX10, IDO1)were screened out in this study. Together, these results supplemented the landscape of immune checkpoints in fungal infection, which may serve as potential therapeutic targets for C. albicans infection. Moreover, the genes with the most relevant for C. albicans infection were identified in this study.

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“…In addition, further studies are required using mammalian models to evaluate the persistence of ex vivo -stimulated mDCs in vivo , their capacity to migrate to the lymph nodes, as well as their safety and potential immunogenic potential. Future in vivo studies should also include direct comparisons of the feasibility, safety, and efficacy of ex vivo -pulsed mDCs with other potentially promising cell therapeutics (e.g., adoptive T-cell transfer or mold-reactive CAR T-cells) ( 4 , 37 , 38 ) and non-cellular immune enhancement strategies such as immune checkpoint blockade ( 39 ).…”

Section: Discussionmentioning

confidence: 99%

CcpA- and Shm2-Pulsed Myeloid Dendritic Cells Induce T-Cell Activation and Enhance the Neutrophilic Oxidative Burst Response to Aspergillus fumigatus

et al. 2021

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Aspergillus fumigatus causes life-threatening opportunistic infections in immunocompromised patients. As therapeutic outcomes of invasive aspergillosis (IA) are often unsatisfactory, the development of targeted immunotherapy remains an important goal. Linking the innate and adaptive immune system, dendritic cells are pivotal in anti-Aspergillus defense and have generated interest as a potential immunotherapeutic approach in IA. While monocyte-derived dendritic cells (moDCs) require ex vivo differentiation, antigen-pulsed primary myeloid dendritic cells (mDCs) may present a more immediate platform for immunotherapy. To that end, we compared the response patterns and cellular interactions of human primary mDCs and moDCs pulsed with an A. fumigatus lysate and two A. fumigatus proteins (CcpA and Shm2) in a serum-free, GMP-compliant medium. CcpA and Shm2 triggered significant upregulation of maturation markers in mDCs and, to a lesser extent, moDCs. Furthermore, both A. fumigatus proteins elicited the release of an array of key pro-inflammatory cytokines including TNF-α, IL-1β, IL-6, IL-8, and CCL3 from both DC populations. Compared to moDCs, CcpA- and Shm2-pulsed mDCs exhibited greater expression of MHC class II antigens and stimulated stronger proliferation and IFN-γ secretion from autologous CD4+ and CD8+ T-cells. Moreover, supernatants of CcpA- and Shm2-pulsed mDCs significantly enhanced the oxidative burst in allogeneic neutrophils co-cultured with A. fumigatus germ tubes. Taken together, our in vitro data suggest that ex vivo CcpA- and Shm2-pulsed primary mDCs have the potential to be developed into an immunotherapeutic approach to tackle IA.

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Protective Activity of Programmed Cell Death Protein 1 Blockade and Synergy With Caspofungin in a Murine Invasive Pulmonary Aspergillosis Model

Cited by 25 publications

References 15 publications

Blockade of the PD-1/PD-L1 Immune Checkpoint Pathway Improves Infection Outcomes and Enhances Fungicidal Host Defense in a Murine Model of Invasive Pulmonary Mucormycosis

Blockade of the PD-1/PD-L1 Immune Checkpoint Pathway Improves Infection Outcomes and Enhances Fungicidal Host Defense in a Murine Model of Invasive Pulmonary Mucormycosis

Single-cell immune checkpoint landscape of PBMCs stimulated with Candida albicans

CcpA- and Shm2-Pulsed Myeloid Dendritic Cells Induce T-Cell Activation and Enhance the Neutrophilic Oxidative Burst Response to Aspergillus fumigatus

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