A preclinical model to investigate the role of surgically‐induced inflammation in tumor responses to intraoperative photodynamic therapy

Davis, Richard W.; Papasavvas, Emmanouil; Klampatsa, Astero; Putt, Mary; Montaner, Luis J.; Culligan, Melissa; McNulty, Sally; Friedberg, Joseph S.; Simone, Charles B.; Singhal, Sunil; Albelda, Steven Μ.; Cengel, Keith A.; Busch, Theresa M.

doi:10.1002/lsm.22934

Cited by 14 publications

(16 citation statements)

References 106 publications

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“…These data indicate that IDO plays an important role in the regulation of immune tolerance to antigens released from dying cells and suggest that PDT-induced tumor cells death may be one of the triggers leading to increased immunopathology. IL-6 was previously shown to be induced by PDT in vitro and in vivo but also in cancer patients [31,35]. The reports on its impact on the antitumor efficacy of PDT were discordant showing either negative [36], positive [37] or no effect [38].…”

Section: Discussionmentioning

confidence: 99%

Inhibition of IDO leads to IL-6-dependent systemic inflammation in mice when combined with photodynamic therapy

Wachowska

Stachura

Tonecka

et al. 2020

Cancer Immunol Immunother

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It was previously reported that the activation of antitumor immune response by photodynamic therapy (PDT) is crucial for its therapeutic outcome. Excessive PDT-mediated inflammation is accompanied by immunosuppressive mechanisms that protect tissues from destruction. Thus, the final effect of PDT strongly depends on the balance between the activation of an adoptive arm of immune response and a range of activated immunosuppressive mechanisms. Here, with flow cytometry and functional tests, we evaluate the immunosuppressive activity of tumor-associated myeloid cells after PDT. We investigate the antitumor potential of PDT combined with indoleamine 2,3-dioxygenase 1 (IDO) inhibitor in the murine 4T1 and E0771 orthotopic breast cancer models. We found that the expression of IDO, elevated after PDT, affects the polarization of T regulatory cells and influences the innate immune response. Our results indicate that, depending on a therapeutic scheme, overcoming IDO-induced immunosuppressive mechanisms after PDT can be beneficial or can lead to a systemic toxic reaction. The inhibition of IDO, shortly after PDT, activates IL-6-dependent toxic reactions that can be diminished by the use of anti-IL-6 antibodies. Our results emphasize that deeper investigation of the physiological role of IDO, an attractive target for immunotherapies of cancer, is of great importance.

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Section: Discussionmentioning

confidence: 99%

Inhibition of IDO leads to IL-6-dependent systemic inflammation in mice when combined with photodynamic therapy

Wachowska

Stachura

Tonecka

et al. 2020

Cancer Immunol Immunother

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“…These inflammatory mediators play a critical role in the activation and recruitment of immune cells at the irradiated tumor site. However, surgically induced IL‐6 is thought to have a negative impact on the efficacy of PDT . Here, we discuss how PDT induces immunostimulatory cell death that eventually leads to the activation of the adaptive immune system and antitumor immunity (Fig.…”

Section: Stimulation Of the Innate Immune Systemmentioning

confidence: 99%

The Course of Immune Stimulation by Photodynamic Therapy: Bridging Fundamentals of Photochemically Induced Immunogenic Cell Death to the Enrichment of T‐Cell Repertoire

Nath

Obaid

Hasan

2019

Photochem & Photobiology

106

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Photodynamic therapy (PDT) is a potentially immunogenic and FDA‐approved antitumor treatment modality that utilizes the spatiotemporal combination of a photosensitizer, light and oftentimes oxygen, to generate therapeutic cytotoxic molecules. Certain photosensitizers under specific conditions, including ones in clinical practice, have been shown to elicit an immune response following photoillumination. When localized within tumor tissue, photogenerated cytotoxic molecules can lead to immunogenic cell death (ICD) of tumor cells, which release damage‐associated molecular patterns and tumor‐specific antigens. Subsequently, the T‐lymphocyte (T cell)–mediated adaptive immune system can become activated. Activated T cells then disseminate into systemic circulation and can eliminate primary and metastatic tumors. In this review, we will detail the multistage cascade of events following PDT of solid tumors that ultimately lead to the activation of an antitumor immune response. More specifically, we connect the fundamentals of photochemically induced ICD with a proposition on potential mechanisms for PDT enhancement of the adaptive antitumor response. We postulate a hypothesis that during the course of the immune stimulation process, PDT also enriches the T‐cell repertoire with tumor‐reactive activated T cells, diversifying their tumor‐specific targets and eliciting a more expansive and rigorous antitumor response. The implications of such a process are likely to impact the outcomes of rational combinations with immune checkpoint blockade, warranting investigations into T‐cell diversity as a previously understudied and potentially transformative paradigm in antitumor photodynamic immunotherapy.

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“…These studies demonstrated that neutrophil activity is critical for tumor control under conditions in which direct tumor cell kill by PDT is not enough to provide for complete response. The clinical treatment of malignant pleural mesothelioma may represent one such scenario, as intraoperative PDT of mesothelioma generated an overall survival of 31.7 months despite a generally much earlier recurrence of disease .…”

Section: Introductionmentioning

confidence: 99%

Luminol Chemiluminescence Reports Photodynamic Therapy‐Generated Neutrophil Activity In Vivo and Serves as a Biomarker of Therapeutic Efficacy

Davis

Snyder

Miller

et al. 2018

Photochem & Photobiology

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Inflammatory cells, most especially neutrophils, can be a necessary component of the anti-tumor activity occurring after administration of photodynamic therapy. Generation of neutrophil responses has been suggested to be particularly important in instances when the delivered PDT dose is insufficient. In these cases, the release of neutrophil granules and engagement of anti-tumor immunity may play an important role in eliminating residual disease. Herein, we utilize in vivo imaging of luminol chemiluminescence to non-invasively monitor neutrophil activation after PDT administration. Studies were performed in the AB12 murine model of mesothelioma, treated with Photofrin-PDT. Luminol-generated chemiluminescence increased transiently 1h after PDT, followed by a subsequent decrease at 4h after PDT. The production of luminol signal was not associated with the influx of Ly6G+ cells, but was related to oxidative burst, as an indicator of neutrophil function. Most importantly, greater levels of luminol chemiluminescence 1h after PDT was prognostic of a complete response at 90 days after PDT. Taken together, this research supports an important role for early activity by Ly6G+ cells in the generation of long-term PDT responses in mesothelioma, and it points to luminol chemiluminescence as a potentially useful approach for preclinical monitoring of neutrophil activation by PDT.

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A preclinical model to investigate the role of surgically‐induced inflammation in tumor responses to intraoperative photodynamic therapy

Cited by 14 publications

References 106 publications

Inhibition of IDO leads to IL-6-dependent systemic inflammation in mice when combined with photodynamic therapy

Inhibition of IDO leads to IL-6-dependent systemic inflammation in mice when combined with photodynamic therapy

The Course of Immune Stimulation by Photodynamic Therapy: Bridging Fundamentals of Photochemically Induced Immunogenic Cell Death to the Enrichment of T‐Cell Repertoire

Luminol Chemiluminescence Reports Photodynamic Therapy‐Generated Neutrophil Activity In Vivo and Serves as a Biomarker of Therapeutic Efficacy

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