RESUMO
The response rate of anti-PD therapy in most cancer patients remains low. Therapeutic drug and tumor-infiltrating lymphocytes (TILs) are usually obstructed by the stromal region within tumor microenvironment (TME) rather than distributed around tumor cells, thus unable to induce the immune response of cytotoxic T cells. Here, we constructed the cationic thermosensitive lipid nanoparticles IR780/DPPC/BMS by introducing cationic NIR photosensitizer IR-780 iodide (IR780) modified lipid components, thermosensitive lipid DPPC and PD-1/PD-L1 inhibitor BMS202 (BMS). Upon laser irradiation, IR780/DPPC/BMS penetrated into deep tumor, and reduced cancer-associated fibroblasts (CAFs) around tumor cells to remodel the spatial distribution of TILs in TME. Interestingly, the cationic IR780/DPPC/BMS could capture released tumor-associated antigens (TAAs), thereby enhancing the antigen-presenting ability of DCs to activate cytotoxic T lymphocytes. Moreover, IR780/DPPC/BMS initiated gel-liquid crystal phase transition under laser irradiation, accelerating the disintegration of lipid bilayer structure and leading to the responsive release of BMS, which would reverse the tumor immunosuppression state by blocking PD-1/PD-L1 pathway for a long term. This combination treatment can synergistically exert the antitumor immune response and inhibit the tumor growth and metastasis.
Assuntos
Antígeno B7-H1/imunologia , Lipossomos/farmacologia , Neoplasias/tratamento farmacológico , Receptor de Morte Celular Programada 1/imunologia , Acetamidas/química , Acetamidas/farmacologia , Antígeno B7-H1/antagonistas & inibidores , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Tolerância Imunológica/efeitos dos fármacos , Imunoterapia/métodos , Indóis/química , Indóis/farmacologia , Lipossomos/química , Terapia com Luz de Baixa Intensidade , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Linfócitos do Interstício Tumoral/efeitos da radiação , Nanopartículas/química , Neoplasias/imunologia , Neoplasias/patologia , Neoplasias/radioterapia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Piridinas/química , Piridinas/farmacologia , Linfócitos T Citotóxicos/efeitos dos fármacos , Linfócitos T Citotóxicos/efeitos da radiação , Microambiente Tumoral/efeitos dos fármacosAssuntos
Balneologia/métodos , Fototerapia/métodos , Psoríase/terapia , Pele/citologia , Células Th17/efeitos da radiação , Raios Ultravioleta , Terapia Ultravioleta/métodos , Adulto , Feminino , Fontes Termais , Humanos , Islândia , Inflamação , Interleucinas/metabolismo , Leucócitos Mononucleares/metabolismo , Masculino , Pessoa de Meia-Idade , Psoríase/sangue , Água do Mar , Índice de Gravidade de Doença , Pele/efeitos da radiação , Linfócitos T Citotóxicos/citologia , Linfócitos T Citotóxicos/efeitos da radiação , Células Th1/citologia , Células Th1/efeitos da radiação , Células Th17/citologia , Interleucina 22RESUMO
LESSONS LEARNED: Percutaneous thermal ablation combined with in situ granulocyte-macrophage colony-stimulating factor cytokine therapy was technically feasible and well tolerated.No significant clinical or immunologic responses were seen. BACKGROUND: Melanoma tumor-derived heat-shock proteins (HSPs) and HSP-peptide complexes can elicit protective antitumor responses. The granulocyte-macrophage colony-stimulating factor (GM-CSF) chemokine can also promote uptake and processing by professional antigen presenting cells (APCs). On this basis, we designed a pilot study of percutaneous thermal ablation as a means to induce heat-shock protein vaccination plus GM-CSF to determine safety and preliminary antitumor activity of this combination. MATERIALS AND METHODS: This study was designed to assess overall safety of percutaneous ablation combined with GM-CSF for unresectable, metastatic melanoma including uveal and mucosal types. All patients received heat-shock therapy (42°C for 30 minutes), then received one of three treatments: (a) intralesional GM-CSF (500 mcg standard dose); (b) radiofrequency ablation (RFA) + GM-CSF; or (c) cryoablation plus GM-CSF. The primary endpoint of the study was the induction of endogenous HSP70 and melanoma-specific cytotoxic T lymphocytes (CTL). RESULTS: Nine patients (three per study arm) were enrolled. No dose-limiting toxicity was observed as specified per protocol. All patients developed progressive disease and went on to receive alternative therapy. Median overall survival (OS) was 8.2 months (95% confidence interval [CI] 2-17.2). The study was not powered to detect a difference in clinical outcome among treatment groups. CONCLUSION: Percutaneous thermal ablation plus GM-CSF was well tolerated, technically feasible, and demonstrated an acceptable adverse event profile comparable to conventional RFA and cryoablation. While HSP70 was induced following therapy, the degree of HSP70 elevation was not associated with clinical outcome or induced CTL responses. While percutaneous thermal ablation plus GM-CSF combinations including checkpoint inhibitors could be considered in future studies, the use of GM-CSF remains experimental and for use in the context of clinical trials.
Assuntos
Criocirurgia/efeitos adversos , Fator Estimulador de Colônias de Granulócitos e Macrófagos/uso terapêutico , Hipertermia Induzida/efeitos adversos , Imunoterapia/efeitos adversos , Melanoma/terapia , Neoplasias Cutâneas/terapia , Idoso , Idoso de 80 Anos ou mais , Terapia Combinada , Criocirurgia/métodos , Estudos de Viabilidade , Feminino , Proteínas de Choque Térmico HSP70/metabolismo , Humanos , Hipertermia Induzida/métodos , Imunoterapia/métodos , Injeções Intralesionais , Estimativa de Kaplan-Meier , Masculino , Melanoma/imunologia , Melanoma/mortalidade , Melanoma/patologia , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Projetos Piloto , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/patologia , Linfócitos T Citotóxicos/efeitos dos fármacos , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/efeitos da radiação , Resultado do TratamentoRESUMO
AIMS: Our previous studies have demonstrated that as a mitochondria-targeting cancer phototherapy, high-fluence, low-power laser irradiation (HF-LPLI) results in oxidative damage that induces tumor cell apoptosis. In this study, we focused on the immunological effects of HF-LPLI phototherapy and explored its antitumor immune regulatory mechanism. RESULTS: We found not only that HF-LPLI treatment induced tumor cell apoptosis but also that HF-LPLI-treated apoptotic tumor cells activated macrophages. Due to mitochondrial superoxide anion burst after HF-LPLI treatment, tumor cells displayed a high level of phosphatidylserine oxidation, which mediated the recognition and uptake by macrophages with the subsequent secretion of cytokines and generation of cytotoxic T lymphocytes. In addition, in vivo results showed that HF-LPLI treatment caused leukocyte infiltration into the tumor and efficaciously inhibited tumor growth in an EMT6 tumor model. These phenomena were absent in the respiration-deficient EMT6 tumor model, implying that the HF-LPLI-elicited immunological effects were dependent on the mitochondrial superoxide anion burst. INNOVATION: In this study, for the first time, we show that HF-LPLI mediates tumor-killing effects via targeting photoinactivation of respiratory chain oxidase to trigger a superoxide anion burst, leading to a high level of oxidatively modified moieties, which contributes to the phenotypic changes in macrophages and mediates the antitumor immune response. CONCLUSION: Our results suggest that HF-LPLI may be an effective cancer treatment modality that both eradicates the treated primary tumors and induces an antitumor immune response via photoinactivation of respiratory chain oxidase to trigger superoxide anion burst.
Assuntos
Neoplasias/imunologia , Neoplasias/metabolismo , Fototerapia , Animais , Apoptose/efeitos da radiação , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos da radiação , Citocinas/biossíntese , Modelos Animais de Doenças , Transporte de Elétrons , Feminino , Humanos , Terapia com Luz de Baixa Intensidade/métodos , Ativação de Macrófagos/imunologia , Ativação de Macrófagos/efeitos da radiação , Macrófagos/imunologia , Macrófagos/metabolismo , Macrófagos/efeitos da radiação , Camundongos , Mitocôndrias/metabolismo , Mitocôndrias/efeitos da radiação , NADPH Oxidases/metabolismo , Neoplasias/patologia , Neoplasias/terapia , Oxirredução/efeitos da radiação , Fototerapia/métodos , Espécies Reativas de Oxigênio/metabolismo , Superóxidos/metabolismo , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/metabolismo , Linfócitos T Citotóxicos/efeitos da radiação , Carga Tumoral/efeitos da radiação , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
OBJECTIVE: Ultraviolet-A1 (UVA1) phototherapy is effective for a variety of dermatological diseases. We examined the effectiveness and reliability of low-dose UVA1 phototherapy (60 kJ/m2/treatment) in patients suffering from systemic lupus erythematosus (SLE). We studied the changes in immunological parameters. METHODS: The patients received a 9-week course of phototherapy according to the following regimen: five times a week during the first 3 weeks, three times a week during the second 3 weeks and twice during the last 3 weeks. Among other things, we analysed the proportions of T helper 1 (Th1), Th2, T cytotoxic (Tc1) and Tc2 cell populations in the peripheral blood of patients by flow cytometric detection of intracytoplasmic interferon gamma (IFN-gamma) and interleukin 4 (IL-4). RESULTS: Our study showed the improvement of clinical symptoms determined by the subjective clinical disease activity scoring and the SLE Disease Activity Index (SLEDAI). By the end of UVA1 phototherapy, the mean value of SLEDAI had decreased from 7.2+/-5.6 to 0.9+/-1.8, which was significant (P = 0.005). Immunological investigations detected a decrease in the frequency of IFN-gamma-producing Th1 and Tc1 cells and a decrease in the Th1/Th2 and Tc1/Tc2 ratios after UVA1 therapy. CONCLUSION: According to the literature, IFN-gamma has a pathogenic role in the development of SLE. We observed a decreased proportion of IFN-gamma-secreting cells, which we think is presumably one of the beneficial effects of UVA1 therapy. On the basis of our study, UVA1 phototherapy does seem to be an effective adjuvant in the treatment of SLE patients.
Assuntos
Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/radioterapia , Subpopulações de Linfócitos T/efeitos da radiação , Terapia Ultravioleta , Adulto , Idoso , Fracionamento da Dose de Radiação , Feminino , Humanos , Interferon gama/biossíntese , Interleucina-4/biossíntese , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Subpopulações de Linfócitos T/imunologia , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/efeitos da radiação , Células Th1/imunologia , Células Th1/efeitos da radiação , Células Th2/imunologia , Células Th2/efeitos da radiação , Resultado do TratamentoRESUMO
Exposure to ultraviolet B (UV-B) light is recognized to induce suppression of certain immune responses, particularly delayed hypersensitivity. However, its effect on cytotoxic T lymphocyte (CTL) activity, of major importance in the resistance to viruses and tumours, has not been assessed to the same extent. In this study five normal subjects, seropositive for herpes simplex virus (HSV), underwent a standard course of broadband UV-B therapy, as used in the treatment of psoriasis. They received whole-body irradiation thrice weekly for four weeks with incremental doses dependent on skin type. Blood samples were taken immediately before, at two time points during, and at the end of the therapy. An HSV-specific CTL assay was performed using autologous B cells transformed with Epstein-Barr virus as targets. No consistent modulation in CTL activity was obtained as a result of the therapy. The CTLs were separated into CD4 and CD8 subsets by positive selection and, again, no effect of irradiation on CTL activity within each of these two populations was observed. In contrast, the natural killer (NK) cell activity, assessed by the lysis of K562 cells, was significantly reduced at the first time point after the initiation of the phototherapy in all five subjects, and it continued to decline as the treatment progressed. Thus a differential effect of UV-B exposure on cytotoxic activity has been demonstrated: the HSV-specific CTL response is unchanged, while the NK response is suppressed.