RESUMO
This article reviews penile squamous cell carcinoma (PSCC), a rare genitourinary cancer that has been increasing in prevalence. It discusses emerging therapies, focusing on immunotherapy, vaccine therapy, and cell-based treatments, especially in the context of human papillomavirus-related PSCC. Factors influencing these therapies are discussed. These include the immune microenvironment, programmed cell death ligand-1 expression, and tumor immune cell infiltration. This article also highlights immune checkpoint inhibitors and related clinical trials. This review supports the use of personalized medicine in treating PSCC. It stresses the need for collaborative studies and data sharing to create specific treatment plans and achieve better outcomes.
Assuntos
Carcinoma de Células Escamosas , Imunoterapia , Neoplasias Penianas , Humanos , Neoplasias Penianas/terapia , Neoplasias Penianas/imunologia , Masculino , Imunoterapia/métodos , Carcinoma de Células Escamosas/terapia , Carcinoma de Células Escamosas/imunologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Microambiente Tumoral/imunologiaRESUMO
Penile squamous cell carcinoma (PSCC) occurs more frequently in some developing countries compared to developed countries. Infection with HIV and/or high-risk human papillomavirus (hrHPV) are risk factors for penile cancer development. The tumor microenvironment of PSCC may predict prognosis and may inform on the best targets for immunotherapy. We evaluated the immune microenvironment of penile tumors histologically, and determined whether and/or how HIV and/or hrHPV infections affect this tumor microenvironment. We conducted a prospective analytical cross-sectional study in which penile cancer tumors from 35 patients presenting at the University Teaching Hospital in Lusaka, Zambia were histologically staged and assessed for presence of tumor infiltrating immune cells and expression of immune checkpoints. Immunohistochemistry was used to evaluate immune checkpoints and infiltrating immune cells, while multiplex real-time polymerase chain reaction was used for hrHPV genotyping. The median age of all participants was 55 years. About 24% had advanced histological stage, 83% were HIV+, and 63% had hrHPV detected in their tumors using multiplex real-time polymerase chain reaction. PDL1 expression was significantly higher in HIV- participants than HIV+ participants (p = 0.02). Tumors with multiple hrHPV infections had a significantly higher number of cells expressing TIM3 than those with one hrHPV (p = 0.04). High grade tumors had a significantly higher infiltrate of FoxP3+ cells (p = 0.02), CD68+ cells (p = 0.01), CD163+ cells (p = 0.01), LAG3+ cells (p = 0.01), PD1+ cells (p = 0.01) and TIM3+ cells (p = 0.03) when compared with low grade tumours. There was significant moderate to strong positive correlation of cells expressing PD1 and LAG3 (â´ = 0.69; p = 0.0001), PD1 and TIM3 (â´ = 0.49; p = 0.017) and TIM3 and LAG3 PDL1 (â´ = 0.61; p = 0.001). In conclusion, the tumor microenvironment of penile squamous cell carcinoma seems to be affected by both HIV and HPV infections. TIM3 appears to be a potential therapeutic target in PSCC patients with hrHPV infections.
Assuntos
Carcinoma de Células Escamosas , Infecções por HIV , Infecções por Papillomavirus , Neoplasias Penianas , Microambiente Tumoral , Adulto , Idoso , Humanos , Masculino , Pessoa de Meia-Idade , Antígeno B7-H1/metabolismo , Antígeno B7-H1/genética , Carcinoma de Células Escamosas/virologia , Carcinoma de Células Escamosas/imunologia , Carcinoma de Células Escamosas/patologia , Estudos Transversais , Infecções por HIV/imunologia , Infecções por HIV/complicações , Infecções por HIV/virologia , Infecções por HIV/patologia , Papillomavirus Humano , Linfócitos do Interstício Tumoral/imunologia , Infecções por Papillomavirus/imunologia , Infecções por Papillomavirus/virologia , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/patologia , Neoplasias Penianas/virologia , Neoplasias Penianas/patologia , Neoplasias Penianas/imunologia , Estudos Prospectivos , Microambiente Tumoral/imunologiaRESUMO
INTRODUCTION: Penile carcinomas are rare tumors throughout Europe. Therefore, little attention is drawn to this disease. That makes it important to study tumor-associated key metrics and relate these to known data on penile neoplasias. MATERIALS AND METHODS: A cohort of 60 well-defined penile invasive carcinomas with known human papillomavirus (HPV) infection status was investigated. Data on tumor type, grading and staging were recorded. Additionally, data on the peri- and intratumoral immune cell infiltrate in a semiquanititave manner applying an HE stain were assessed. RESULTS: Our study showed a significant correlation of immune cell infiltrate and pT stage with overall survival. Therefore, in a subset of tumors, PD-L1 staining was applied. For tumor proportion score (TPS), 26 of 30 samples (87%) were scored >0%. For the immune cell score (IC), 28 of 30 samples (93%) were defined as >0% and for CPS, 29 of 30 samples (97%) scored >0. PD-L1 expression was not associated with overall survival. CONCLUSION: PD-L1 is expressed in penile carcinomas, providing a rationale for targeted therapy with checkpoint inhibitors. We were able to show that immune reaction appears to be prognostically relevant. These data enhance the need for further studies on the immune cell infiltrate in penile neoplasias and show that PD-L1 expression is existent in our cohort, which may be a potential target for checkpoint inhibitor therapy.
Assuntos
Antígeno B7-H1/análise , Carcinoma de Células Escamosas/química , Carcinoma de Células Escamosas/imunologia , Carcinoma de Células Escamosas/patologia , Infecções por Papillomavirus/imunologia , Infecções por Papillomavirus/patologia , Neoplasias Penianas/química , Neoplasias Penianas/imunologia , Neoplasias Penianas/patologia , Microambiente Tumoral , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas/virologia , Estudos de Coortes , Humanos , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Neoplasias Penianas/virologiaRESUMO
Penile cancer is a rare but highly lethal cancer, and therapeutic options for patients presenting with lymph nodal disease are very limited. Adoptive cell therapy (ACT) using tumor-infiltrating lymphocytes (TIL) was shown to provide durable objective response in patients with metastatic melanoma and TIL have been expanded from solid tumors at rates between 70 and 90% depending on the specific diagnosis. We evaluated whether TIL could be expanded from surgical specimens of patients with penile cancer. Tumor samples from metastatic lymph nodes obtained at the time of inguinal lymph node dissection were collected, minced into fragments, placed in individual wells of a 24-well plate, and propagated in high dose IL-2 for four weeks. The phenotype of expanded TILs was assessed by flow cytometry and their anti-tumor reactivity was assessed by IFN-γ ELISA. TIL were expanded from 11 out of 12 (91.6%) samples of metastatic lymph nodes. Expanded TIL were predominantly CD3+ (mean 67.5%, SD 19.4%) with a mean of 46.8% CD8+ T cells (SD 21.1%). Five out of 11 samples (45.4%) from expanded TIL secreted IFN-γ in response to autologous tumor. TIL expansion and phenotype of expanded T cell lymphocytes were independent of previous HPV infection and treatment with neoadjuvant chemotherapy. This is the first report demonstrating successful expansion of tumor-reactive TIL from penile cancer patients, which support development of ACT strategies using TIL for the treatment of advanced and recurrent penile cancer.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Carcinoma de Células Escamosas/imunologia , Linfócitos do Interstício Tumoral/imunologia , Infecções por Papillomavirus/imunologia , Neoplasias Penianas/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas/terapia , Carcinoma de Células Escamosas/virologia , Humanos , Linfonodos/imunologia , Metástase Linfática/imunologia , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Infecções por Papillomavirus/terapia , Infecções por Papillomavirus/virologia , Neoplasias Penianas/terapia , Neoplasias Penianas/virologiaRESUMO
PURPOSE: Nearly half of penile cancers are related to human papillomavirus (HPV) infection. Investigations of tumor- and HPV-specific T cell reactivity in regional lymph nodes (LNs) from patients with penile cancer are warranted. MATERIALS AND METHODS: In this study, single-cell suspensions from LNs and peripheral blood from 11 patients with penile cancer were stained with antibodies for lymphocyte markers and analyzed by fluorescence-activated cell sorting (FACS). DNA was extracted from the tumor tissue and HPV status was investigated by PCR. RESULTS: T-cell reactivity against autologous tumor-extract and against the HPV-vaccine Gardasil® was tested by flow-cytometric assay of specific cell-mediated immune response in activated whole blood (FASCIA). CD4+/CD8+ ratios were significantly lower in HPV positive LNs (p<0.05). Immune responses to tumor extract assessed by blast transformation and expansion in vitro, of either CD4+ or CD8+ T-cells, were found in 9 of 13 LNs (69%). 5 of 6 tested patients demonstrated T cell recognition of tumor-associated antigen(s). In HPV-positive patients, dose-dependent T cell responses against L1 (late) HPV proteins (Gardasil vaccine) were demonstrated. CONCLUSIONS: LN-derived T cells from patients with penile cancer recognize tumor antigen(s) and in HPV-positive cases, there is a response against L1 (late) HPV proteins, being constituents of the Gardasil vaccine.
Assuntos
Antígenos de Neoplasias/imunologia , Linfonodos/imunologia , Papillomaviridae/imunologia , Neoplasias Penianas/imunologia , Neoplasias Penianas/virologia , Idoso , Idoso de 80 Anos ou mais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Vacina Quadrivalente Recombinante contra HPV tipos 6, 11, 16, 18/imunologia , Humanos , Imunofenotipagem , Ativação Linfocitária , Masculino , Pessoa de Meia-Idade , Papillomaviridae/genética , Proteínas Virais/imunologiaRESUMO
Penile squamous cell carcinomas (SCCs) are common tumors in older horses, with poor prognosis mostly due to local invasion and recurrence. These tumors are thought to be mainly caused by Equus caballus papillomavirus type 2 (EcPV-2). The aim of this study is to characterize the tumor immune environment (TIME) in equine penile tumors. Equine penile epithelial tumors (17 epSCCs; 2 carcinomas in situ, CIS; 1 papilloma, P) were retrospectively selected; immune infiltrate was assessed by histology and immunohistochemistry; RT-qPCR tested the expression of selected chemokines and EcPV-2 DNA and RNA. The results confirmed EcPV-2-L1 DNA in 18/20 (90%) samples. L1 expression was instead retrieved in 13/20 cases (65%). The samples showed an increased infiltration of CD3+lymphocytes, macrophages (MAC387; IBA1), plasma cells (MUM1), and FoxP3+lymphocytes in the intra/peritumoral stroma when compared to extratumoral tissues (p < 0.05). Only MAC387+neutrophils were increased in EcPV-2high viral load samples (p < 0.05). IL12/p35 was differentially expressed in EcPVhigh and EcPVlow groups (p = 0.007). A significant decrease of IFNG and IL2 expression was highlighted in TGFB1-positive samples (p < 0.05). IBA1 and CD20 were intratumorally increased in cases where IL-10 was expressed (p < 0.005). EpSCCs may represent a good spontaneous model for the human counterpart. Further prospective studies are needed in order to confirm these preliminary results.
Assuntos
Carcinoma de Células Escamosas/imunologia , Carcinoma de Células Escamosas/veterinária , Cavalos/imunologia , Neoplasias Penianas/imunologia , Neoplasias Penianas/veterinária , Microambiente Tumoral/imunologia , Animais , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/virologia , Citocinas/metabolismo , Modelos Animais de Doenças , Humanos , Antígeno Ki-67/metabolismo , Masculino , Papillomaviridae/fisiologia , Neoplasias Penianas/patologia , Neoplasias Penianas/virologia , Carga Viral , Proteínas Virais/metabolismoRESUMO
The incidence of penile squamous cell carcinoma (PSCC) has increased in developed countries over the past decades owing to increased human papilloma virus (HPV) exposure. Despite successful surgical treatment of locoregional PSCC, effective treatment options for advanced disease are limited. The prognosis of patients with bulky nodal and metastatic PSCC is dismal and new management approaches are urgently needed. Genomic analyses have provided transformative knowledge on the genomic and molecular landscape and tumour microenvironment of PSCC. Around one-quarter of patients with metastatic PSCC have clinically actionable genomic alterations in mechanistic target of rapamycin, DNA repair and receptor tyrosine kinase pathways. These patients might benefit from combined and sequential targeted therapies. HPV vaccination might be another therapeutic option as PSCC is genetically similar to other HPV-driven cancers. In addition, 40-60% of PSCC tumours show strong PDL1 expression, and the frequency of mutational signatures suggestive of immunotherapy resistance is low, pointing to potential utility of immunotherapy for PSCC. Finally, identification of the composition of the penile microbiota and its biological role might lead to new cancer prevention and treatment strategies.
Assuntos
Carcinoma de Células Escamosas/genética , Neoplasias Penianas/genética , Carcinoma de Células Escamosas/imunologia , Feminino , Regulação Neoplásica da Expressão Gênica , Predisposição Genética para Doença/genética , Genômica , Humanos , Imunoterapia , Masculino , Neoplasias Penianas/tratamento farmacológico , Neoplasias Penianas/imunologia , Microambiente Tumoral/genética , Microambiente Tumoral/imunologiaRESUMO
BACKGROUND: Indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan (Trp) catabolism have been demonstrated to play an important role in tumor immunosuppression. This study examined the expression and catalytic activity of IDO1 in penile squamous cell carcinoma (PSCC) and explored their clinical significance. METHODS: IDO1 expression level, serum concentrations of Trp and kynurenine (Kyn) were examined in 114 PSCC patients by immunohistonchemistry and solid-phase extraction-liquid chromatography-tandem mass spectrometry. The survival was analyzed using Kaplan-Meier method and the log-rank test. Hazard ratio of death was analyzed via univariate and multivariate Cox regression. Immune cell types were defined by principal component analysis. The correlativity was assessed by Pearson's correlation analysis. RESULTS: The expression level of IDO1 in PSCC cells was positively correlated with serum Kyn concentration and Kyn/Trp radio (KTR; both P < 0.001) but negatively correlated with serum Trp concentration (P = 0.001). Additionally, IDO1 up-regulation in cancer cells and the increase of serum KTR were significantly associated with advanced N stage (both P < 0.001) and high pathologic grade (P = 0.008 and 0.032, respectively). High expression level of IDO1 in cancer cells and serum KTR were associated with short disease-specific survival (both P < 0.001). However, besides N stage (hazard radio [HR], 6.926; 95% confidence interval [CI], 2.458-19.068; P < 0.001) and pathologic grade (HR, 2.194; 95% CI, 1.021-4.529; P = 0.038), only serum KTR (HR, 2.780; 95% CI, 1.066-7.215; P = 0.036) was an independent predictor for PSCC prognosis. IDO1 expression was positively correlated with the expression of interferon-γ (IFNγ, P < 0.001) and immunosuppressive markers (programmed cell death protein 1, cytotoxic T-lymphocyte-associated protein 4 and programmed death-ligand 1 and 2; all P < 0.05), and the infiltration of immune cells (including cytotoxic T lymphocytes, regulatory T lymphocytes, tumor-associated macrophages, and myeloid-derived suppressor cells; all P < 0.001) in PSCC tissues. Furthermore, the expression of IDO1 was induced by IFNγ in a dose-dependent manner in PSCC cells. CONCLUSIONS: IFNγ-induced IDO1 plays a crucial role in immunoediting and immunosuppression in PSCC. Additionally, serum KTR, an indicator of IDO1 catabolic activity, can be utilized as an independent prognostic factor for PSCC.
Assuntos
Carcinoma de Células Escamosas/imunologia , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Neoplasias Penianas/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígeno B7-H1/metabolismo , Biomarcadores Tumorais/metabolismo , Antígeno CTLA-4/metabolismo , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Humanos , Tolerância Imunológica , Cinurenina/sangue , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Neoplasias Penianas/enzimologia , Neoplasias Penianas/metabolismo , Neoplasias Penianas/patologia , Prognóstico , Taxa de Sobrevida , Triptofano/sangue , Regulação para Cima , Adulto JovemRESUMO
Current chemotherapeutic treatment for advanced penile squamous cell carcinoma has substantial side effects and no randomized data to support an overall survival benefit. Immunotherapy with checkpoint blockade is currently being tested in penile cancer patients in clinical trials. The high PD-L1 expression and CD8+ T-cell infiltration in penile cancer represent a promising prospect for immunotherapy response in the treatment of locally advanced disease. For efficacious immunotherapy treatment, a better understanding of the tumor microenvironment (TME) is critical. Here we use the structure revealed by cancer immunograms to define current knowledge of the penile cancer TME as a backbone for future research. PATIENT SUMMARY: Advanced penile cancer has a poor prognosis with a need for more effective therapy. In this manuscript we describe the potential of immunotherapy as a new treatment modality in penile cancer.
Assuntos
Imunoterapia , Neoplasias Penianas/patologia , Neoplasias Penianas/terapia , Microambiente Tumoral , Humanos , Masculino , Neoplasias Penianas/imunologiaRESUMO
Human papilloma virus (HPV) infections are one of the most common sexually transmitted diseases. We present the case of a 77-year-old Caucasian male with enormous genital warts of the penis, scrotum, groins and anus. Lesions were excised by electrosurgery. The histological examination revealed Condylomata gigantea as well as an invasive perianal squamous cell carcinoma. Mucosal "low-risk" HPV type 6 was detected. The patient had a history of an immunosuppressing disease. During the 4-year follow-up, multiple relapses occurred. Thus, particularly in immunosuppressed patients, early prophylactic HPV vaccination seems to be indicated for use in the prevention of HPV-associated mutilating and life-threatening disease. Vaccination should also protect from "low-risk" HPV.
Assuntos
Neoplasias do Ânus/virologia , Tumor de Buschke-Lowenstein/virologia , Carcinoma de Células Escamosas/virologia , Papillomavirus Humano 6/patogenicidade , Hospedeiro Imunocomprometido , Infecções Oportunistas/virologia , Neoplasias Penianas/virologia , Idoso , Neoplasias do Ânus/diagnóstico , Neoplasias do Ânus/imunologia , Neoplasias do Ânus/terapia , Biópsia , Tumor de Buschke-Lowenstein/diagnóstico , Tumor de Buschke-Lowenstein/imunologia , Tumor de Buschke-Lowenstein/terapia , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/imunologia , Carcinoma de Células Escamosas/terapia , Testes de DNA para Papilomavírus Humano , Papillomavirus Humano 6/imunologia , Humanos , Masculino , Infecções Oportunistas/diagnóstico , Infecções Oportunistas/imunologia , Infecções Oportunistas/terapia , Neoplasias Penianas/diagnóstico , Neoplasias Penianas/imunologia , Neoplasias Penianas/terapia , Resultado do TratamentoRESUMO
The host's immune system plays a pivotal role in many tumor types, including squamous cell carcinomas (SCCs). We aim to identify immunological prognosticators for lymph node metastases (LNM) and disease-specific survival (DSS) in penile SCC. For this retrospective observational cohort study, penile SCC patients (n = 213) treated in the Netherlands Cancer Institute, were selected if sufficient formalin-fixed, paraffin-embedded tumor material was available. Analysis included previously described high-risk human papilloma virus (hrHPV) status, immunohistochemical scores for classical and non-classical human leukocyte antigen (HLA) class I, programmed death ligand-1 (PD-L1) expression, and novel data on tumor-infiltrating macrophages and cytotoxic an regulatory T-cells. Clinicopathological characteristics and extended follow-up were also included. Regression analyses investigated relationships of the immune parameters with LNM and DSS. In the total cohort, diffuse PD-L1 tumor-cell expression, CD163+ macrophage infiltration, non-classical HLA class I upregulation, and low stromal CD8+ T-cell infiltration were all associated with LNM. In the multivariable model, only tumor PD-L1 expression remained a significant predictor for LNM (odds ratio (OR) 2.8, p = 0.05). hrHPV negativity and diffuse PD-L1 tumor-cell expression were significantly associated with poor DSS and remained so upon correction for clinical parameters [hazard ratio (HR) 9.7, p < 0.01 and HR 2.8, p = 0.03]. The only immune factor with different expression in HPV+ and HPV- tumors was PD-L1, with higher PD-L1 expression in the latter (p = 0.03). In the HPV- cohort (n = 158), LNM were associated with diffuse PD-L1 tumor-cell expression, high intratumoral CD163+ macrophage infiltration, and low number of stromal CD8+ T-cells. The first two parameters were also linked to DSS. In the multivariable regression model, diffuse PD-L1 expression remained significantly unfavorable for DSS (HR 5.0, p < 0.01). These results emphasize the complexity of the tumor microenvironment in penile cancer and point toward several possible immunotherapy targets. Here described immune factors can aid risk-stratification and should be evaluated in clinical immunotherapy studies to ultimately lead to patient tailored treatment.
Assuntos
Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/imunologia , Neoplasias Penianas/diagnóstico , Neoplasias Penianas/imunologia , Microambiente Tumoral/imunologia , Idoso , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Biomarcadores , Seguimentos , Humanos , Fatores Imunológicos , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Países Baixos , Razão de Chances , Infecções por Papillomavirus/classificação , Infecções por Papillomavirus/genética , Prognóstico , Linfócitos T CitotóxicosRESUMO
Penile squamous cell carcinoma (PeSCC) is a rare tumor and advanced PeSCC is associated with poor survival due to the aggressiveness of the disease and lack of effective systemic therapies. We describe for the first time a case with advanced chemoradiation refractory PeSCC who had documented response to active immunotherapy with the immune checkpoint inhibitor, anti-programmed death-1 monoclonal antibody Nivolumab. The patient suffered from a poor prognosis human papillomavirus-negative PeSCC, with a somatic inactivation mutation of cyclin-dependent kinase inhibitor 2A (CDKN2A) gene in tumor cells, and treatment with Nivolumab resulted in a partial response to therapy and significant tumor shrinkage. Histology transitions and alterations in tumor-infiltrating cytotoxic CD8 T-cell lymphocytes, programmed death ligand-1 expression on tumor cells and immune cells in tumor lesion biopsies pretreatment and posttreatment with Nivolumab were observed and described. In conclusion, in patients with metastatic PeSCC active immunotherapy combinations with an anti-programmed death-1/programmed death ligand-1 agent may be beneficial and further relative clinical studies are required.
Assuntos
Antineoplásicos/uso terapêutico , Carcinoma de Células Escamosas/terapia , Imunoterapia/métodos , Linfócitos do Interstício Tumoral/imunologia , Nivolumabe/uso terapêutico , Neoplasias Penianas/terapia , Linfócitos T Citotóxicos/imunologia , Carcinoma de Células Escamosas/imunologia , Carcinoma de Células Escamosas/mortalidade , Quimiorradioterapia , Inibidor p16 de Quinase Dependente de Ciclina/genética , Resistencia a Medicamentos Antineoplásicos , Evolução Fatal , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/genética , Estadiamento de Neoplasias , Neoplasias Penianas/imunologia , Neoplasias Penianas/mortalidade , Receptor de Morte Celular Programada 1/imunologia , Receptor de Morte Celular Programada 1/metabolismo , Carga TumoralRESUMO
Two major pathways of penile carcinogenesis are known: human papillomavirus (HPV)-induced penile cancer and HPV-negative cancers associated with chronic dermatoses. Therefore, modern measures for prevention of penile cancer may for example include prophylactic HPV vaccination. The resulting Bcell-mediated immunity to HPV capsid proteins is effective protection against future HPV infections. Contrarily when treating existing HPV infections or HPV-associated cancers an antigen-specific Tcell immunity is necessary. To date, screening and treatment of precancerous lesions to prevent penile cancer are not established in the German health care program and the highly expected therapeutic HPV vaccines are still on the horizon. In this article, we focus on possible strategies to prevent HPV-related penile cancer on different levels of carcinogenesis.
Assuntos
Carcinoma de Células Escamosas/diagnóstico , Infecções por Papillomavirus/diagnóstico , Neoplasias Penianas/diagnóstico , Carcinoma de Células Escamosas/imunologia , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/prevenção & controle , Circuncisão Masculina , Detecção Precoce de Câncer , Diagnóstico Precoce , Epitopos/imunologia , Humanos , Masculino , Papillomaviridae/imunologia , Infecções por Papillomavirus/imunologia , Infecções por Papillomavirus/patologia , Infecções por Papillomavirus/prevenção & controle , Vacinas contra Papillomavirus/imunologia , Vacinas contra Papillomavirus/uso terapêutico , Neoplasias Penianas/imunologia , Neoplasias Penianas/patologia , Neoplasias Penianas/prevenção & controle , Pênis/patologia , Fimose/complicações , Fimose/diagnóstico , Fimose/imunologia , Lesões Pré-Cancerosas/diagnóstico , Lesões Pré-Cancerosas/imunologia , Lesões Pré-Cancerosas/patologia , Lesões Pré-Cancerosas/prevenção & controle , Linfócitos T/imunologiaRESUMO
Background: Evidence suggests that natural antibodies developed after HPV16 infection may protect some women but not men against subsequent HPV16 reacquisition. Less is known whether antibodies developed following HPV16 infection are protective among men who have sex with men (MSM).Methods: Four hundred seventy-five MSM from the Human Papillomavirus Infection in Men (HIM) study were tested for serum antibodies to HPV16 L1 using enzyme-linked immunosorbent assays, and for anal and genital HPV16 DNA using PCR consensus primer system (PGMY 09/11). Adjusted Cox regression was used to evaluate whether baseline HPV16 seropositivity impacts subsequent genital or anal HPV16 DNA.Results: The risk of subsequent genital HPV16 [aHR = 1.05, 95% confidence interval (CI) = 0.66-1.68] and anal HPV16 infections among MSM (aHR = 2.34, 95% CI = 0.92-5.98) was similar or nonsignificantly higher in HPV16-seropositive than HPV16-seronegative MSM. The risk of genital HPV16 was also similar between HPV16-seronegative and HPV16-seropositive MSM in the highest tertile of HPV16 antibody levels and when restricting to those with new sex partners during follow-up (P > 0.20). Among the 118 MSM who were HPV16 seropositive, 90% remained HPV16 seropositive up to 4 years later. When tested together, MSM with the highest antibody titers (top tertile) had similar levels to females (mean = 130.3 vs. 134.5 EU/mL, P = 0.84).Conclusions: Despite years of HPV16 seropositivity persistence and antibody titers comparable with females, this study suggested no evidence of HPV16 natural antibodies protecting against subsequent genital or anal HPV16 infection in MSM.Impact: This could help partially explain the high incidence of genital and anal HPV16 infection and related anal cancer seen in middle-aged and older MSM. Cancer Epidemiol Biomarkers Prev; 27(4); 496-502. ©2018 AACR.
Assuntos
Anticorpos Antivirais/sangue , Neoplasias do Ânus/prevenção & controle , Papillomavirus Humano 16/imunologia , Infecções por Papillomavirus/imunologia , Neoplasias Penianas/prevenção & controle , Minorias Sexuais e de Gênero/estatística & dados numéricos , Adulto , Idoso , Anticorpos Antivirais/imunologia , Neoplasias do Ânus/imunologia , Neoplasias do Ânus/virologia , Brasil , Proteínas do Capsídeo/imunologia , DNA Viral/isolamento & purificação , Seguimentos , Papillomavirus Humano 16/genética , Papillomavirus Humano 16/isolamento & purificação , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Oncogênicas Virais/imunologia , Infecções por Papillomavirus/sangue , Infecções por Papillomavirus/diagnóstico , Infecções por Papillomavirus/virologia , Neoplasias Penianas/imunologia , Neoplasias Penianas/virologia , Estudos Prospectivos , Testes Sorológicos , Adulto JovemRESUMO
Penile squamous cell carcinoma (SCC) is primarily treated by surgical resection. Locally advanced and metastatic diseases require a multidisciplinary treatment approach. However, mortality and morbidity remain high, and novel molecular and immunotherapeutic targets are actively being sought. We investigated the expression of immune-checkpoint markers in penile cancers. Fifty-three invasive penile SCCs diagnosed between 1985 and 2013 were retrieved from our surgical pathology archives. Representative formalin-fixed, paraffin-embedded archival blocks were used for the construction of 2 high-density tissue microarrays. Tissue microarrays were stained with immunohistochemistry for PD-L1, FOXP3, CD8, and Ki-67. PD-L1 was investigated using rabbit monoclonal anti-PD-L1 antibody (Cell Signaling, Boston, MA; E1L3N, 1:100). Overall, 21 (40%) of 53 penile SCCs had positive PD-L1 expression. PD-L1 was expressed by a significant proportion of advanced penile SCC. Forty-four percent (15/34) of stage pT2 or more SCC and 38% (6/16) of tumors with lymph node metastasis were positive for PD-L1. PD-L1 expression did not correlate with patient age, tumor location, histologic subtype, tumor stage, anatomic depth of invasion, or tumor grade. FOXP3 expression in tumoral immune cells was found in 26 (49%) of 53 cases. FOXP3 expression in stromal immune cells correlated with tumor thickness (P = .0086). The ratio of CD8/FOXP3 was greater than 1 in 62% of cases in tumor-infiltrating immune cells and 34% of cases in stromal immune cells. Our current study is the largest to assess expression of PD-L1 in a clinically well-annotated North American cohort of penile SCC. Our findings support a rationale for targeting immune-checkpoint inhibitor pathways in advanced penile SCC.
Assuntos
Antígeno B7-H1/análise , Biomarcadores Tumorais/análise , Linfócitos T CD8-Positivos/imunologia , Carcinoma de Células Escamosas/imunologia , Fatores de Transcrição Forkhead/análise , Linfócitos do Interstício Tumoral/imunologia , Neoplasias Penianas/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Baltimore , Biópsia , Linfócitos T CD8-Positivos/patologia , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/secundário , Carcinoma de Células Escamosas/terapia , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Metástase Linfática , Linfócitos do Interstício Tumoral/patologia , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Invasividade Neoplásica , Estadiamento de Neoplasias , Neoplasias Penianas/mortalidade , Neoplasias Penianas/patologia , Neoplasias Penianas/terapia , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Células Estromais/imunologia , Células Estromais/patologia , Análise Serial de Tecidos , Microambiente TumoralRESUMO
BACKGROUND: Kaposi sarcoma (KS) is a cancer with an incidence in patients after transplantation (Tx) that is 500 times greater than that in the healthy population. The risk of KS increases significantly during therapy, especially when immunosuppressive therapy with cyclosporine A (CsA) is used. Most cases of KS develop during the first 2 years after transplantation. After a KS diagnosis, it is recommended to reduce the doses of immunosuppressive medications. Conversion of immunosuppressive treatment into mammalian target of rapamycin (m-TOR) inhibitors is strongly suggested. PATIENTS AND METHODS: We present the case of a 65-year-old man with end-stage renal disease (ESRD) of unknown etiology, who had kidney transplantation in 2008. Immunosuppressive protocol was based on CsA, mycophenolate mofetil (MMF) and prednisolone (PRE). In 2011, during the dermatological consultation, on the penis glans a purple stain of uneven surface was noted. Histology study revealed the presence of KS. The treatment was modified. The patient was converted from CsA to everolimus. Before converting, the creatinine concentration was 1.79 mg/dl and proteinuria less than 0.3 g/day. RESULTS: The change in the scheme of immunosuppresion from CsA to everolimus was performed to treat the Kaposi sarcoma. Gradually, within a year, the KS was cured. However, the graft function deteriorated, and the graft was lost in one-years' time. CONCLUSION: We present the first documented case of KS in the genital area of a kidney patient. The reduction in the strength of immunosuppression, and the introduction of an m-TOR inhibitor, may have contributed to the deterioration of kidney function, however it was substantial in the treatment of KS.
Assuntos
Everolimo/uso terapêutico , Hospedeiro Imunocomprometido , Transplante de Rim/efeitos adversos , Neoplasias Penianas/imunologia , Sarcoma de Kaposi/imunologia , Idoso , Ciclosporina/efeitos adversos , Feminino , Humanos , Terapia de Imunossupressão/efeitos adversos , Imunossupressores/uso terapêutico , Masculino , Ácido Micofenólico/efeitos adversos , Prednisolona/uso terapêuticoRESUMO
BACKGROUND: Despite aggressive multimodal therapy, locally advanced and/or metastatic penile squamous cell carcinoma (SqCC) is associated with significant morbidity and mortality, indicating a need for new therapeutic options. Given the emerging clinical utility of immunotherapeutics, we sought to assess the incidence and potential clinical significance of PD-L1 expression in penile SqCC. PATIENTS AND METHODS: Using an anti-PD-L1 primary antibody (clone 5H1), immunohistochemistry was carried out on whole tumor sections from 37 patients with penile SqCC treated at our institution between 2005 and 2013. PD-L1-positive tumors were defined as those with membranous staining in ≥5% of tumor cells. Association between PD-L1 expression and clinicopathologic parameters was examined using Fisher's exact test. Correlation between PD-L1 expression in primary tumors and matched metastases was assessed using the Spearman rank correlation coefficient (ρ). The difference in cancer-specific mortality between PD-L1-positive and -negative groups was examined using the log-rank test. RESULTS: Twenty-three (62.2%) of 37 primary tumors were positive for PD-L1 expression, and there was strong positive correlation of PD-L1 expression in primary and metastatic samples (ρ = 0.72; 0.032 < P < 0.036). Primary tumor PD-L1 expression was significantly associated with usual type histology (P = 0.040) and regional lymph node metastasis (P = 0.024), as well as decreased cancer-specific survival (P = 0.011). CONCLUSIONS: The majority of primary penile SqCC tumors express PD-L1, which is associated with high-risk clinicopathologic features and poor clinical outcome. These data provide a rational basis for further investigation of anti-PD-1 and anti-PD-L1 immunotherapeutics in patients with advanced penile SqCC.
Assuntos
Antígeno B7-H1/genética , Biomarcadores Tumorais/genética , Carcinoma de Células Escamosas/genética , Neoplasias Penianas/genética , Idoso , Carcinoma de Células Escamosas/imunologia , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/terapia , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Imunoterapia , Linfócitos do Interstício Tumoral/metabolismo , Linfócitos do Interstício Tumoral/patologia , Masculino , Pessoa de Meia-Idade , Neoplasias Penianas/imunologia , Neoplasias Penianas/patologia , Neoplasias Penianas/terapia , Fatores de RiscoRESUMO
PURPOSE: Loss of expression of HLA class I is a mechanism of immune evasion in various cancers that is often associated with a worse patient outcome. We analyzed HLA expression in a large cohort with penile cancer in relation to clinical outcome. MATERIALS AND METHODS: We used penile cancer tissue blocks from 168 patients who underwent surgical resection between 2000 and 2009 to construct tissue microarrays. Immunohistochemical staining was done with antibodies directed against classic and nonclassic HLA molecules. HLA expression was scored semiquantitatively, divided into 3 expression groups and correlated with clinicopathological variables, including HPV and survival. Survival analysis was performed using the Kaplan-Meier method and Cox proportional hazards models. RESULTS: Complete and partial loss of total classic HLA class I was observed in 32% and 50% of cases, and up-regulation of HLA-E and G in 16% and 13%, respectively. When corrected for relevant clinical parameters, partial HLA-A loss was significantly associated with decreased survival overall (HR 2.3, 95% CI 1.1-4.6) and in HPV negative patients alone (HR 3.4, 95% CI 1.4-8.4). Abnormal HLA-B/C, E or G expression levels were not associated with survival. CONCLUSIONS: To our knowledge this is the first study to describe a link between HLA expression and the clinical outcome of penile cancer. HLA down-regulation occurs frequently and partial loss of HLA-A is an independent predictor of poor survival in HPV negative patients. Complete understanding of the mechanisms and relevance of HLA down-regulation and immune evasion in regard to the clinical outcome will contribute to the future design of immunotherapy interventions.
Assuntos
Antígenos HLA/biossíntese , Papillomaviridae/isolamento & purificação , Neoplasias Penianas/imunologia , Neoplasias Penianas/virologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Genes MHC Classe I , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Penianas/genética , Neoplasias Penianas/mortalidade , Estudos Prospectivos , Taxa de SobrevidaRESUMO
Human papillomavirus infection (HPV) has been implicated in penile cancer, and although the annual incidence is estimated to be 1,570 in the United States, there are areas of the world in which the incidence is as much as 20-fold higher. Ample data in the literature support testing and vaccination against HPV-related cervical cancer, but for men and penile cancer, these data are lacking. However, some preliminary data would suggest that HPV not only plays an important role in a significant subset of patients with penile cancer but also may be a target for penile cancer prevention as well via initiation of a vaccination program in high-risk male populations.
Assuntos
Alphapapillomavirus/imunologia , Infecções por Papillomavirus/imunologia , Vacinas contra Papillomavirus/imunologia , Neoplasias Penianas/imunologia , Alphapapillomavirus/fisiologia , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Humanos , Masculino , Infecções por Papillomavirus/prevenção & controle , Infecções por Papillomavirus/virologia , Vacinas contra Papillomavirus/uso terapêutico , Neoplasias Penianas/prevenção & controle , Neoplasias Penianas/virologia , Pênis/imunologia , Pênis/patologia , Pênis/virologia , Prognóstico , Fatores de RiscoRESUMO
Besides the well-known systemic immune deficiency, also a regional immune deficiency, labeled as "immunocompromised district" (ICD), has been documented and focused in the recent years. The objective of the study is to gain more insights into the mechanisms involved in systemic and local immune destabilization. A 35-year-old, homosexual, and drug-addicted HIV+ man presented with a single nodule of Kaposi sarcoma (KS) located on the penis, where a slow to heal herpes zoster had appeared 2 months before. It has been assumed that the unusual penile location of herpes zoster facilitated the outbreak of KS in the affected dermatome because of a viral damage to sensory nerve fibers of the same dermatome. This damage, by interfering with the immunoregulatory function of neuropeptides released by nerve endings in that area, may have caused a regional alteration of the immune control favoring the local onset of the "opportunistic" angiogenic tumor (KS). In a few words, an ICD took place in an immunocompromised patient, thus introducing a more vulnerable site in an already vulnerable subject. The present case is the second one in the literature to document an ICD in the setting of preexisting systemic immune deficiency.