RESUMO
BACKGROUND: To characterize the expression of co-signaling molecules PD-L1, PD-1, and B7-H3 in cutaneous squamous cell carcinoma (cSCC) by immune status. METHODS: We retrospectively analyzed 66 cases of cSCC treated with surgical resection from 2012 to 2015. Immunostained tumor sections were analyzed for percent of tumor cells expressing PD-L1 (Tum-PD-L1%), B7-H3 (Tum-B7-H3%), density of peri and intratumoral CD8 T cells (CD8 density), proportion of CD8 T cells expressing PD-1 (CD8-PD-1%) and of tumor-infiltrating immune cells (TII) expressing PD-L1 (TII-PD-L1%). RESULTS: Of 66 cases, 42 were immunocompetent, 24 immunosuppressed (13 organ transplant, 8 HIV+, 3 other). Defining positive expression at > 5%, 26% of tumors were positive for PD-L1, 85% for B7-H3, 80% had CD8 T cells that expressed PD-1 and 55% had TII that expressed PD-L1. Tum-B7-H3% was significantly higher (median 60 vs. 28%, p = 0.025) in immunocompetent vs. immunosuppressed patients, including when factoring in cause of immunosuppression. No significant difference in Tum-PD-L1%, TII-PD-L1%, CD8 density, or CD8-PD-1% was observed. Tumors from HIV+ patients lacked PD-L1 expression, and had lower B7-H3% (median 2.5 vs. 60%, p = 0.007), and higher CD8 density (median 75% vs. 40%, p = 0.04) compared to immunocompetent patients. Higher tumor grade (Rs = 0.34, p = 0.006) and LVI (Rs = 0.61, p < 0.001) were both associated with higher Tum-PD-L1%. CONCLUSION: cSCC showed expression of PD-L1 on tumor in 26% of cases, and high tumor B7-H3 expression (85%) and PD-1 expression on CD8 TILs (80%). Tumor B7-H3 expression was significantly higher in immunocompetent vs. immunosuppressed patients, largely driven by very low expression in HIV+ patients.
Assuntos
Antígenos B7/metabolismo , Antígeno B7-H1/metabolismo , Carcinoma de Células Escamosas/metabolismo , Imunocompetência/imunologia , Hospedeiro Imunocomprometido/imunologia , Terapia de Imunossupressão , Receptor de Morte Celular Programada 1/metabolismo , Neoplasias Cutâneas/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/metabolismo , Linfócitos T CD8-Positivos/imunologia , Carcinoma de Células Escamosas/imunologia , Carcinoma de Células Escamosas/patologia , Feminino , Seguimentos , Humanos , Linfócitos do Interstício Tumoral/imunologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/patologiaRESUMO
Given the inherent resistance to apoptosis that characterizes cancer, the targeting of alternative pathways is an attractive strategy to improve anti-tumor therapy. Endoplasmic reticulum (ER) stress, which is basally activated in many cancers, and the subsequent activation of autophagy represent novel cancer treatment targets. While these associated pathways are often protective and promote cell survival, when excessive, ER stress results in autophagic cell death. Therefore, depending on the circumstances, either inhibition or activation of ER stress and autophagy can improve cancer therapy. This review provides an update on how ER stress relates to autophagy, and how these associated pathways can serve dual functions to promote survival or cell death in cancer. Furthermore, it lays out a spectrum of potential pharmacological agents and combinatorial approaches that target these pathways to enhance tumor cell kill.
Assuntos
Antineoplásicos/uso terapêutico , Autofagia/fisiologia , Resistencia a Medicamentos Antineoplásicos , Retículo Endoplasmático/fisiologia , Neoplasias/tratamento farmacológico , Transdução de Sinais , Estresse Fisiológico , Animais , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Autofagia/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Terapia Combinada , Retículo Endoplasmático/efeitos dos fármacos , Retículo Endoplasmático/metabolismo , Humanos , Camundongos , Neoplasias/fisiopatologia , Neoplasias/radioterapia , Transdução de Sinais/efeitos dos fármacosRESUMO
PURPOSE: To determine whether MLN8054, an Aurora kinase A (Aurora-A) inhibitor causes radiosensitization in androgen-insensitive prostate cancer cells in vitro and in vivo. METHODS AND MATERIALS: In vitro studies consisted of culturing PC3 and DU145 prostate cancer cells and then immunoblotting Aurora A and phospho-Aurora A after radiation and/or nocodazole with MLN8054. Phases of the cell cycle were measured with flow cytometry. PC3 and DU145 cell lines were measured for survival after treatment with MLN8054 and radiation. Immunofluorescence measured γ-H2AX in the PC3 and DU145 cells after treatment. In vivo studies looked at growth delay of PC3 tumor cells in athymic nude mice. PC3 cells grew for 6 to 8 days in mice treated with radiation, MLN8054, or combined for 7 more days. Tumors were resected and fixed on paraffin and stained for von Willebrand factor, Ki67, and caspase-3. RESULTS: In vitro inhibition of Aurora-A by MLN8054 sensitized prostate cancer cells, as determined by dose enhancement ratios in clonogenic assays. These effects were associated with sustained DNA double-strand breaks, as evidenced by increased immunofluorescence for γ-H2AX and significant G2/M accumulation and polyploidy. In vivo, the addition of MLN8054 (30 mg/kg/day) to radiation in mouse prostate cancer xenografts (PC3 cells) significantly increased tumor growth delay and apoptosis (caspase-3 staining), with reduction in cell proliferation (Ki67 staining) and vascular density (von Willebrand factor staining). CONCLUSION: MLN8054, a novel small molecule Aurora-A inhibitor showed radiation sensitization in androgen-insensitive prostate cancer in vitro and in vivo. This warrants the clinical development of MLN8054 with radiation for prostate cancer patients.
Assuntos
Benzazepinas/uso terapêutico , Neoplasias da Próstata/radioterapia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Tolerância a Radiação/efeitos dos fármacos , Radiossensibilizantes/uso terapêutico , Androgênios/uso terapêutico , Animais , Apoptose/efeitos da radiação , Aurora Quinase A , Aurora Quinases , Caspase 3/análise , Ciclo Celular , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Quebras de DNA de Cadeia Dupla , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Histonas/análise , Humanos , Immunoblotting/métodos , Antígeno Ki-67/análise , Masculino , Camundongos , Camundongos Nus , Nocodazol/uso terapêutico , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologiaRESUMO
Genotoxic agents have long targeted apoptotic cell death as a primary means of treating cancer. However, the presence of cellular defects in many cancers has contributed to an acquired resistance to apoptotic cell death, lowering the effectiveness of chemo- and radiotherapies. The mechanisms by which cells achieve this resistance to treatment are still being investigated, but an alternative approach is the study of cell death pathways that are mechanistically distinct from apoptosis. These pathways, including autophagy and necrosis, have arisen as attractive targets for cancer therapy. This review will discuss apoptosis, autophagy, and necrosis in the context of tumorigenesis and drug resistance, as well as provide an up-to-date preclinical and clinical review of inhibitors targeting these cell death pathways for multiple cancer types. The goal of these studies is to identify molecular targets that will enhance the efficacy and specificity of current cancer therapies.