Cytotoxic antimelanoma drugs suppress the activation of M2 macrophages

Fujimura, Taku; Kakizaki, Aya; Kambayashi, Yahiko; Sato, Yota; Tanita, Kayo; Lyu, Chunbing; Furudate, Sadanori; Aiba, Setsuya

doi:10.1111/exd.13417

Cited by 22 publications

(28 citation statements)

References 34 publications

(68 reference statements)

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“…We also evaluated other Th2 chemokines (CCL24 and CCL26) that might contribute to the pathogenesis of BP by the recruitment of eosinophils, and CCL2, which is reported to recruit the precursor of macrophages and is increased in the serum of BP patients . Minocycline and cyclosporine, respectively, significantly decreased the production of CCL2, CCL24 and CCL26 from M2 macrophages (Figure ).…”

Section: Resultsmentioning

confidence: 99%

Minocycline decreases Th2 chemokines from M2 macrophages: Possible mechanisms for the suppression of bullous pemphigoid by traditional bullous disease drugs

Tanita

Fujimura

Sato

et al. 2018

Experimental Dermatology

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Minocycline/tetracycline is clinically used for the treatment of bullous pemphigoid (BP), and its clinical benefits are superior to those of prednisolone when considering adverse events. Although the clinical benefits of minocycline/tetracycline are well known, its immunosuppressive mechanisms are still unclear. In this study, we investigated the immunomodulatory effects of traditional anti-BP drugs (minocycline, nicotinic acid amide, dexamethasone and cyclosporine) on CD163 M2 macrophages in vitro, with special focus on the production of CCL18 and CCL22, both of which are produced by CD163 M2 macrophages in the lesional skin of BP and are increased in the serum of BP patients. Minocycline decreased the production of CCL22, CCL24 and CCL26 as well as CCL2 from M2 macrophages. CCL18 from M2 macrophages was decreased by dexamethasone and cyclosporine, but not decreased by minocycline. These data suggest that the clinical benefit of minocycline is partially explained by its suppressive effects against the production of specific Th2 chemokines from M2 macrophages, which should contribute to the recruitment of Th2 cells and eosinophils in the lesional skin of BP patients.

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Section: Resultsmentioning

confidence: 99%

Minocycline decreases Th2 chemokines from M2 macrophages: Possible mechanisms for the suppression of bullous pemphigoid by traditional bullous disease drugs

Tanita

Fujimura

Sato

et al. 2018

Experimental Dermatology

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“…DPCP also led to nodal or visceral metastasis regression in four of the patients , thus suggesting the potential for an abscopal effect with this topically applied immunotherapy. A recent 2‐patient case series showed that topical immunotherapy has limited effect on internal disease, but that combined treatment with the PD‐1 inhibitor nivolumab led to pronounced internal metastasis regression . Within an ongoing trial treating melanoma patients with topical DPCP formulated in a non‐volatile, aqueous solvent as an Investigational New Drug (ClinicalTrials.gov number, NCT01711684), we have observed a remarkable tumor response in one patient on concurrent pembrolizumab therapy.…”

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confidence: 82%

Definite regression of cutaneous melanoma metastases upon addition of topical contact sensitizer diphencyprone to immune checkpoint inhibitor treatment

Gulati

Postow

Wolchok

et al. 2016

Experimental Dermatology

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Abbreviations: DPCP, diphencyprone; PD-1, programmed death-1. Key words: diphencyprone -immunotherapy -melanomapembrolizumab Accepted for publication 31 March 2016The immune checkpoint inhibitor pembrolizumab, which targets programmed death-1 (PD-1) receptor, has recently emerged as the standard-of-care treatment for patients with advanced melanoma, with a response rate of 33% (1). Another agent in the realm of immunotherapy used throughout the world, but not currently approved by the Food and Drug Administration in the United States, is the contact sensitizer diphencyprone (DPCP). Topical DPCP has been used in a 50-patient case series of cutaneously metastatic melanoma, with a response rate of 84%. DPCP also led to nodal or visceral metastasis regression in four of the patients (2), thus suggesting the potential for an abscopal effect with this topically applied immunotherapy. A recent 2-patient case series showed that topical immunotherapy has limited effect on internal disease, but that combined treatment with the PD-1 inhibitor nivolumab led to pronounced internal metastasis regression (3). Within an ongoing trial treating melanoma patients with topical DPCP formulated in a non-volatile, aqueous solvent as an Investigational New Drug (ClinicalTrials.gov number, NCT01711684), we have observed a remarkable tumor response in one patient on concurrent pembrolizumab therapy.The patient is a 93-year-old man who underwent resection of his primary acral melanoma harbouring an exon 13 K642E mutation from his right foot ten years ago. Subsequently, he was treated with ipilimumab as well as imatinib, but ultimately progressed with extensive in-transit metastases throughout his right lower extremity, which is when he presented to our institution, not having been on any medical therapy for 6 months (Fig. 1a). The patient received two months of twice weekly topical DPCP applications (0.4% and 0.04% concentrations were alternately used, with the goal being to maintain a tolerable level of inflammation and change concentration as necessary) while on no other therapies for his melanoma, and inflammation was induced as expected, but tumor response was incomplete, with generally only smaller lesions (<1 cm) responding, and larger lesions expanding (Fig. 1b). At this point, the patient discontinued DPCP applications to begin treatment with pembrolizumab (2 mg/kg as intravenous infusion every 3 weeks), but during the three months on pembrolizumab (the median time to response for this agent), his disease rapidly progressed (Fig. 1c). We then elected to restart DPCP applications (again twice weekly) concurrently with pembrolizumab (again every 3 weeks), first only to a region of skin that selectively responded (Fig. 1d), suggesting a synergistic reaction, but these data do not fully exclude the possibility of a delayed response to pembrolizumab. Then applications were extended throughout the skin areas involved with melanoma, with substantial metastasis regression observed (Fig. 1e). In comparison with single-agent DPCP, combinati...

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“…Because the stromal factor on each cancer stem cell is an important factor for TAM stimulation, leading to the induction of specific TAM phenotypes, investigating the immunomodulatory stromal cells in the tumor microenvironment is important for establishing the appropriate immunotherapy for each type of cancer ( 1 , 8 , 9 , 16 , 17 ). In addition, it may be possible to repolarize TAMs into anti-tumor macrophages, such as M1-phenotype macrophages, to suppress tumor progression by modifying the profiles of tumor-infiltrating lymphocytes (TILs) ( 7 , 18 , 19 ). Thus, TAMs could be a target for immunotherapy in skin cancers ( 1 , 2 ).…”

Section: Introductionmentioning

confidence: 99%

Tumor-Associated Macrophages: Therapeutic Targets for Skin Cancer

et al. 2018

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Tumor-associated macrophages (TAMs) and regulatory T cells (Tregs) are significant components of the microenvironment of solid tumors in the majority of cancers. TAMs sequentially develop from monocytes into functional macrophages. In each differentiation stage, TAMs obtain various immunosuppressive functions to maintain the tumor microenvironment (e.g., expression of immune checkpoint molecules, production of Treg-related chemokines and cytokines, production of arginase I). Although the main population of TAMs is immunosuppressive M2 macrophages, TAMs can be modulated into M1-type macrophages in each differential stage, leading to the suppression of tumor growth. Because the administration of certain drugs or stromal factors can stimulate TAMs to produce specific chemokines, leading to the recruitment of various tumor-infiltrating lymphocytes, TAMs can serve as targets for cancer immunotherapy. In this review, we discuss the differentiation, activation, and immunosuppressive function of TAMs, as well as their benefits in cancer immunotherapy.

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Cytotoxic antimelanoma drugs suppress the activation of M2 macrophages

Cited by 22 publications

References 34 publications

Minocycline decreases Th2 chemokines from M2 macrophages: Possible mechanisms for the suppression of bullous pemphigoid by traditional bullous disease drugs

Minocycline decreases Th2 chemokines from M2 macrophages: Possible mechanisms for the suppression of bullous pemphigoid by traditional bullous disease drugs

Definite regression of cutaneous melanoma metastases upon addition of topical contact sensitizer diphencyprone to immune checkpoint inhibitor treatment

Tumor-Associated Macrophages: Therapeutic Targets for Skin Cancer

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