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In this case series, ustekinumab therapy demonstrated efficacy in some patients with severe hidradenitis suppurativa previously treated with adalimumab and/or infliximab. Larger prospective studies are needed to evaluate ustekinumab as a treatment option for recalcitrant hidradenitis suppurativa.
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Fármacos Dermatológicos , Hidradenite Supurativa , Adalimumab/uso terapêutico , Fármacos Dermatológicos/uso terapêutico , Hidradenite Supurativa/tratamento farmacológico , Humanos , Infliximab/uso terapêutico , Ustekinumab/uso terapêuticoRESUMO
Tumor-associated macrophages (TAMs) represent the most abundant leukocyte population in most solid tumors and are greatly influenced by the tumor microenvironment. More importantly, these macrophages can promote tumor growth and metastasis through interactions with other cell populations within the tumor milieu and have been associated with poor outcomes in multiple tumors. In this review, we examine how the tumor microenvironment facilitates the polarization of TAMs. Additionally, we evaluate the mechanisms by which TAMs promote tumor angiogenesis, induce tumor invasion and metastasis, enhance chemotherapeutic resistance, and foster immune evasion. Lastly, we focus on therapeutic strategies that target TAMs in the treatments of cancer, including reducing monocyte recruitment, depleting or reprogramming TAMs, and targeting inhibitory molecules to increase TAM-mediated phagocytosis.
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The programmed death-1 (PD-1) and the PD ligand 1 (PD-L1) interaction represents a key immune checkpoint within the tumor microenvironment (TME), and PD-1 blockade has led to exciting therapeutic advances in clinical oncology. Although IFN-γ-dependent PD-L1 induction on tumor cells was initially thought to mediate the suppression on effector cells, recent studies have shown that PD-L1 is also expressed at high level on tumor-associated macrophages (TAMs) in certain types of tumors. However, the precise role of PD-L1 expression on TAMs in suppressing antitumor immunity within the TME remains to be defined. Using a myeloid-specific Pdl1-knockout mouse model, here we showed definitive evidence that PD-L1 expression on TAMs is critical for suppression of intratumor CD8+ T cell function. We further demonstrated that tumor-derived Sonic hedgehog (Shh) drives PD-L1 expression in TAMs to suppress tumor-infiltrating CD8+ T cell function, leading to tumor progression. Mechanistically, Shh-dependent upregulation of PD-L1 in TAMs is mediated by signal transducer and activator of transcription 3, a cascade that has not been previously reported to our knowledge. Last, single-cell RNA sequencing analysis of human hepatocellular carcinoma revealed that PD-L1 is mainly expressed on M2 TAMs, supporting the clinical relevance of our findings. Collectively, our data revealed an essential role for Shh-dependent PD-L1 upregulation in TAMs in suppressing antitumor immunity within the TME, which could lead to the development of new immunotherapeutic strategies for treating cancer.
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Antígeno B7-H1/metabolismo , Linfócitos T CD8-Positivos/imunologia , Proteínas Hedgehog/metabolismo , Macrófagos Associados a Tumor/imunologia , Animais , Carcinoma Hepatocelular/imunologia , Neoplasias Hepáticas/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais , Microambiente Tumoral/imunologiaRESUMO
BACKGROUND: Preservatives are often necessary components of commercial products. Large-scale North American studies on preservative allergy are limited. OBJECTIVE: To evaluate demographics, positive patch test reactions (PPTRs), clinical relevance, and trends for preservatives tested by the North American Contact Dermatitis Group. METHODS: We conducted a retrospective cross-sectional analysis of North American Contact Dermatitis Group patch testing results of preservatives from 1994 through 2016. RESULTS: A total of 50,799 patients were tested; 11,338 (22.3%) had a PPTR to at least 1 preservative. The most frequent reactions were to methylisothiazolinone 0.2% aqueous (aq) (12.2%), formaldehyde 2% aq (7.8%), formaldehyde 1% aq (7.8%), quaternium-15 2% petrolatum (pet) (7.7%), and methyldibromo glutaronitrile/phenoxyethanol 2% pet (5.1%). Paraben mix 12% pet (1%), iodopropynyl butylcarbamate 0.1% pet (0.4%), benzyl alcohol 1% pet (0.3%), and phenoxyethanol 1% pet (0.2%) had the lowest PPTRs. Linear regression analysis of preservatives tested showed that only methylchloroisothiazolinone/methylisothiazolinone 0.01% aq (parameter estimate, 0.42; 95% CI, 0.17-0.66; P < .005) had a significant increase in PPTRs over time. LIMITATIONS: Collected variables are dependent on clinical judgment. Results may be prone to referral selection bias. CONCLUSIONS: This large North American study provides insight on preservative PPTRs and trends from 1994 through 2016.
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Dermatite Alérgica de Contato/etiologia , Conservantes Farmacêuticos/efeitos adversos , Distribuição por Idade , Canadá/epidemiologia , Estudos Transversais , Dermatite Alérgica de Contato/diagnóstico , Dermatite Alérgica de Contato/epidemiologia , Dermatite Ocupacional/epidemiologia , Dermatite Ocupacional/etiologia , Feminino , Dermatoses da Mão/epidemiologia , Humanos , Hipersensibilidade Imediata/epidemiologia , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Especificidade de Órgãos , Testes do Emplastro , Estudos Retrospectivos , Distribuição por Sexo , Estados Unidos/epidemiologiaRESUMO
The skin is an active immune organ that functions as the first and largest site of defense to the outside environment. Serving as the primary interface between host and pathogen, the skin's early immune responses to viral invaders often determine the course and severity of infection. We review the current literature pertaining to the mechanisms of cutaneous viral invasion for classical skin-tropic, oncogenic, and vector-borne skin viruses. We discuss the skin's evolved mechanisms for innate immune viral defense against these invading pathogens, as well as unique strategies utilized by the viruses to escape immune detection. We additionally explore the roles that demographic and environmental factors, such as age, biological sex, and the cutaneous microbiome, play in altering the host immune response to viral threats.
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Dermatite/etiologia , Suscetibilidade a Doenças , Interações Hospedeiro-Patógeno/imunologia , Evasão da Resposta Imune , Imunidade Inata , Viroses/etiologia , Dermatite/metabolismo , Meio Ambiente , Humanos , Fatores de Risco , Tropismo Viral , Viroses/metabolismo , Viroses/transmissão , Fenômenos Fisiológicos Virais , Vírus/classificação , Vírus/imunologiaRESUMO
Chimeric antigen receptors (CAR) are fusion proteins engineered from antigen recognition, signaling, and costimulatory domains that can be used to reprogram T cells to specifically target tumor cells expressing specific antigens. Current CAR-T cell technology utilizes the patient's own T cells to stably express CARs and has achieved exciting clinical success in the past few years. However, current CAR-T cell therapy still faces several challenges, including suboptimal persistence and potency, impaired trafficking to solid tumors, local immunosuppression within the tumor microenvironment and intrinsic toxicity associated with CAR-T cells. This review focuses on recent strategies to improve the clinical efficacy of CAR-T cell therapy and other exciting CAR approaches currently under investigation, including CAR natural killer (NK) and NKT cell therapies.
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PURPOSE OF REVIEW: The review provides an update on the diagnosis, pathogenesis, and treatment of cutaneous lupus erythematosus (CLE). RECENT FINDINGS: Diagnostic challenges exist in better defining CLE as an independent disease distinct from systemic lupus erythematosus with cutaneous features and further classifying CLE based on clinical, histological, and laboratory features. Recent mechanistic studies revealed more genetic variations, environmental triggers, and immunologic dysfunctions that are associated with CLE. Drug induction specifically has emerged as one of the most important triggers for CLE. Treatment options include topical agents and systemic therapies, including newer biologics such as belimumab, rituximab, ustekinumab, anifrolumab, and BIIB059 that have shown good clinical efficacy in trials. CLE is a group of complex and heterogenous diseases. Future studies are warranted to better define CLE within the spectrum of lupus erythematosus. Better insight into the pathogenesis of CLE could facilitate the design of more targeted therapies.
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Lúpus Eritematoso Cutâneo , Anticorpos Monoclonais Humanizados/uso terapêutico , Humanos , Lúpus Eritematoso Cutâneo/diagnóstico , Lúpus Eritematoso Cutâneo/tratamento farmacológico , Lúpus Eritematoso Cutâneo/etiologia , Rituximab/uso terapêutico , Pele/patologia , Ustekinumab/uso terapêuticoAssuntos
Toxidermias/diagnóstico , Toxidermias/etiologia , Lúpus Eritematoso Cutâneo/induzido quimicamente , Lúpus Eritematoso Cutâneo/diagnóstico , Adolescente , Adulto , Idoso , Criança , Toxidermias/epidemiologia , Humanos , Incidência , Lúpus Eritematoso Cutâneo/epidemiologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto JovemRESUMO
OBJECTIVE: To provide a formal statistical comparison of the efficacy of melanoma detection among different clinical settings. METHODS: A systematic review and meta-analysis of all relevant observational studies on number needed to treat (NNT) in relation to melanoma was performed in MEDLINE. We performed a random-effects model meta-analysis and reported NNTs with 95% confidence intervals (CIs). The subgroup analysis was related to clinical setting. RESULTS: In all, 29 articles including a total of 398,549 biopsies/excisions were analyzed. The overall NNT was 9.71 (95% CI, 7.72-12.29): 22.62 (95% CI, 12.95-40.10) for primary care, 9.60 (95% CI, 6.97-13.41) for dermatology, and 5.85 (95% CI, 4.24-8.27) for pigmented lesion specialists. LIMITATIONS: There is heterogeneity in data reporting and the possibility of missing studies. In addition, the incidence of melanoma varies among clinical settings, which could affect NNT calculations. CONCLUSION: Pigmented lesion specialists have the lowest NNT, followed by dermatologists, suggesting that involving specialists in the diagnosis and treatment of pigmented skin lesions can likely improve patient outcomes.
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Melanoma/epidemiologia , Melanoma/cirurgia , Cirurgia de Mohs/estatística & dados numéricos , Neoplasias Cutâneas/epidemiologia , Neoplasias Cutâneas/cirurgia , Centros Médicos Acadêmicos , Biópsia por Agulha , Procedimentos Cirúrgicos Dermatológicos/métodos , Procedimentos Cirúrgicos Dermatológicos/estatística & dados numéricos , Dermatologistas/estatística & dados numéricos , Feminino , Humanos , Imuno-Histoquímica , Incidência , Masculino , Melanoma/diagnóstico , Cirurgia de Mohs/métodos , Neoplasias Cutâneas/diagnóstico , Resultado do Tratamento , Estados UnidosRESUMO
The growth of hematologic malignant cells can be facilitated by other non-tumor cells within the same microenvironment, including stromal, vascular, immune and mesenchymal stem cells. Macrophages are an integral part of the human innate immune system and the tumor microenvironment. Complex interplays between the malignant hematologic cells and the infiltrating macrophages promote the formation of leukemia, lymphoma or myeloma-associated macrophages. These pro-tumorigenic macrophages in turn play an important part in facilitating tumor growth, metastasis and chemotherapeutic resistance. Previous reports have highlighted the association between tumor-associated macrophages (TAMs) and disease progression in hematologic malignancies. This review summarizes the role of TAMs in different subtypes of leukemia, lymphoma and myeloma, focusing on new insights and targeted therapies.
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Carcinogênese/imunologia , Neoplasias Hematológicas , Imunoterapia/métodos , Leucemia , Macrófagos/imunologia , Microambiente Tumoral , Progressão da Doença , Neoplasias Hematológicas/patologia , Neoplasias Hematológicas/terapia , Humanos , Leucemia/patologia , Leucemia/terapia , Macrófagos/patologiaRESUMO
Tumor-associated macrophages (TAMs) usually display an antiinflammatory M2-like phenotype to facilitate tumor growth. However, what drives M2 polarization of TAMs and how TAMs suppress antitumor immunity within the tumor microenvironment (TME) remain largely undefined. Using several murine tumor models, we showed that hedgehog (Hh) signaling in myeloid cells is critical for TAM M2 polarization and tumor growth. We also found that tumor cells secrete sonic hedgehog (SHH), an Hh ligand, and that tumor-derived SHH drives TAM M2 polarization. Furthermore, Hh-induced functional polarization in TAMs suppresses CD8+ T cell recruitment to the TME through the inhibition of CXCL9 and CXCL10 production by TAMs. Last, we demonstrated that Krüppel-like factor 4 (Klf4) mediates Hh-dependent TAM M2 polarization and the immunosuppressive function. Collectively, these findings highlight a critical role for tumor-derived SHH in promoting TAM M2 polarization, a mechanism for TAM-mediated immunosuppression, and may provide insights into the design of new cancer immunotherapeutic strategies.
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Linfócitos T CD8-Positivos/citologia , Carcinoma Hepatocelular/imunologia , Proteínas Hedgehog/metabolismo , Neoplasias Hepáticas/imunologia , Macrófagos/citologia , Animais , Linhagem Celular Tumoral , Linhagem da Célula , Feminino , Células HEK293 , Humanos , Tolerância Imunológica , Terapia de Imunossupressão , Fator 4 Semelhante a Kruppel , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células Mieloides/citologia , Transplante de Neoplasias , Fenótipo , Receptores CXCR3/metabolismo , Transdução de Sinais , Microambiente Tumoral/imunologiaRESUMO
Tumor-associated macrophages (TAMs), representing most of the leukocyte population in solid tumors, demonstrate great phenotypic heterogeneity and diverse functional capabilities under the influence of the local tumor microenvironment. These anti-inflammatory and protumorigenic macrophages modulate the local microenvironment to facilitate tumor growth and metastasis. In this review, we examine the origin of TAMs and the complex regulatory networks within the tumor microenvironment that facilitate the polarization of TAMs toward a protumoral phenotype. More extensively, we evaluate the mechanisms by which TAMs mediate angiogenesis, metastasis, chemotherapeutic resistance and immune evasion. Lastly, we will highlight novel interventional strategies targeting TAMs in preclinical studies and in early clinical trials that have significant potential in improving efficacy of current chemotherapeutic and/or immunotherapeutic approaches.