Immune Checkpoint Blockade in Human Cancer Therapy: Lung Cancer and Hematologic Malignancies

Janakiram, Murali; Pareek, Vipul; Cheng, Haiying; Narasimhulu, Deepa Maheswari; Zang, Xingxing

doi:10.2217/imt-2016-0001

Cited by 47 publications

(39 citation statements)

References 37 publications

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“…Murine models have shown that blocking any of PD-1 [99,100], PD-L1 [100,101], or PD-L2 [101] has beneficial effects in inhibiting the growth and spread of tumors; conversely, constitutive expression of PD-L1 by tumor cells leads to enhanced resistance to CD8 + T cell-mediated cytolysis [102]. In a series of exciting developments, inhibitors of the PD-1 signaling pathway have shown considerable efficacy in numerous clinical trials involving patients with malignant disease who have failed conventional therapies (reviewed in [103,104]). Thus, in addition to understanding the effects of the PD-1 signaling pathway on fungal pathogenesis (reviewed below), it will be essential to ascertain whether the expanding clinical use of checkpoint inhibitors will alter the susceptibility or severity of fungal infections in patients treated with these immunotherapy agents.…”

Section: Immunoregulatory Signaling Pathwaysmentioning

confidence: 99%

Immunoregulation in Fungal Diseases

2016

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This review addresses specific regulatory mechanisms involved in the host immune response to fungal organisms. We focus on key cells and regulatory pathways involved in these responses, including a brief overview of their broader function preceding a discussion of their specific relevance to fungal disease. Important cell types discussed include dendritic cells and regulatory T cells, with a focus on specific studies relating to their effects on immune responses to fungi. We highlight the interleukin-10, programmed cell death 1, and cytotoxic T lymphocyte-associated protein 4 signaling pathways and emphasize interrelationships between these pathways and the regulatory functions of dendritic cells and regulatory T cells. Throughout our discussion, we identify selected studies best illustrating the role of these cells and pathways in response to specific fungal pathogens to provide a contextual understanding of the tightly-controlled network of regulatory mechanisms critical to determining the outcome of exposure to fungal pathogens. Lastly, we discuss two unique phenomena relating to immunoregulation, protective tolerance and immune reactivation inflammatory syndrome. These two clinically-relevant conditions provide perspective as to the range of immunoregulatory mechanisms active in response to fungi.

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Section: Immunoregulatory Signaling Pathwaysmentioning

confidence: 99%

Immunoregulation in Fungal Diseases

2016

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“…Numerous studies have shown that blockade of the PD-1 signaling pathway can promote enhanced immune responses against cancers by altering important immunomodulatory mechanisms active in established tumor microenvironments (29–31, 43, 44). Having identified that PD-1 and its ligands were upregulated on immune effector cells in the lungs of mice with persistent cryptococcal lung infection, our next objective was to determine whether antibody-mediated blockade of this pathway could improve fungal clearance in this model.…”

Section: Resultsmentioning

confidence: 99%

“…Our interest in studying this pathway in the context of fungal persistence stems from studies demonstrating that PD-1 signaling impairs clearance of some viral (24–26) and bacterial pathogens (27, 28). Furthermore, numerous studies have shown that this pathway promotes tumor immune evasion which has led to the development of potent immune checkpoint inhibitors which effectively treat tumors in mice (29, 30) and humans (reviewed in (31, 32)).…”

Section: Introductionmentioning

confidence: 99%

Anti–PD-1 Antibody Treatment Promotes Clearance of Persistent Cryptococcal Lung Infection in Mice

Roussey

Viglianti

Teitz-Tennenbaum

et al. 2017

The Journal of Immunology

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Activation of immunomodulatory pathways in response to invasive fungi can impair clearance and promote persistent infections. The Programmed Cell Death Protein-1 (PD-1) signaling pathway inhibits immune effector responses against tumors and immune checkpoint inhibitors that block this pathway are being increasingly used as cancer therapy. The objective of the current study was to investigate whether this pathway contributes to persistent fungal infection and to determine whether anti-PD-1 antibody treatment improves fungal clearance. Studies were performed using C57BL/6 mice infected with a moderately virulent strain of Cryptococcus neoformans (52D) which resulted in prolonged elevations in fungal burden and histopathologic evidence of chronic lung inflammation. Persistent infection was associated with increased and sustained expression of PD-1 on lung lymphocytes, including a mixed population of CD4+ T cells. In parallel, expression of the PD-1 ligands, PD-L1 and PD-L2, was similarly upregulated on specific subsets of resident and recruited lung dendritic cells and macrophages. Treatment of persistently-infected mice for four weeks by repetitive administration of neutralizing anti-PD-1 antibody significantly improved pulmonary fungal clearance. Treatment was well tolerated without evidence of morbidity. Immunophenotyping revealed that anti-PD-1 antibody treatment did not alter immune effector cell numbers or myeloid cell activation. Treatment did reduce gene expression of IL-5 and IL-10 by lung leukocytes and promoted sustained upregulation of OX40 by Th1 and Th17 cells. Collectively, this study demonstrates that PD-1 signaling promotes persistent cryptococcal lung infection and identifies this pathway as a potential target for novel immune-based treatments of chronic fungal disease.

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“…They are recognized as inhibitory receptors on T cells and can regulate the activation and tolerance of T cells [11]. Several reports have shown that PD-L1 and PD-L2 have important but opposing roles in modulation of T-cell functions [24,25]. Usually, PD-1/PD-L1 interaction can stimulate the production of IL-4, producing a Th2 response and increasing lung inflammation and airway hyperresponsiveness.…”

Section: Discussionmentioning

confidence: 99%

Activation of Bombesin Receptor Subtype-3 Promotes Antigen-Presenting Action in Human Bronchial Epithelial Cells

Liu

Peng

Liu

et al. 2018

Int Arch Allergy Immunol

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Background: Bombesin receptor subtype-3 (BRS-3) is a member of the bombesin-like peptide receptor family. Our previous studies demonstrated that activation of the human BRS-3 plays a protective role in oxidation-injured human bronchial epithelial cells (HBEC). The present study was designed to determine the role of BRS-3 activation in the antigen-presenting action of HBEC and the corresponding proliferation and differentiation of T cells. Materials and Methods: In vivo, an asthma animal model was established and the expression and distribution of BRS-3 were analyzed by immunocytochemistry. In vitro, 2 kinds of B7 costimulatory molecules, i.e., B7H1 and B7DC, on HBEC were analyzed by flow cytometry. The antigen uptake by HBEC was examined by confocal microscopy and flow cytometry. The antigen-presenting-action-induced proliferation of T cells was determined by MTT assays. IFN-γ and IL-4 levels were measured by ELISA. All studies were performed in the absence or presence of the synthetic peptide P3513. Results: BRS-3 expression was induced in asthma animal models and mainly distributed in bronchial epithelial cells. HBEC express the costimulatory molecules B7H1 and B7DC. BRS-3 activation increased B7H1 expression but decreased B7DC expression on HBEC. BRS-3 activation also increased the antigen uptake by HBEC and the subsequent T cell proliferation. In addition, BRS-3 activation promoted the releases of IFN-γ, but not IL-4, in the supernatant of cocultured HBEC and T cells. Conclusion: These data suggest that HBEC can present antigen to T cells and BRS-3 activation promotes the process of antigen presentation and subsequent T cell proliferation and Th1 differentiation.

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Immune Checkpoint Blockade in Human Cancer Therapy: Lung Cancer and Hematologic Malignancies

Cited by 47 publications

References 37 publications

Immunoregulation in Fungal Diseases

Immunoregulation in Fungal Diseases

Anti–PD-1 Antibody Treatment Promotes Clearance of Persistent Cryptococcal Lung Infection in Mice

Activation of Bombesin Receptor Subtype-3 Promotes Antigen-Presenting Action in Human Bronchial Epithelial Cells

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