RESUMO
BACKGROUND: Determining T cell responses to naturally processed and presented antigens is a critical immune correlate to determine efficacy of an investigational immunotherapeutic in clinical trials. In most cases, minimal epitopes and HLA restriction elements are unknown. RESULTS: Here, we detail the experimental use of ex vivo expanded autologous B cells as antigen presenting cells to overcome the limitation of unknown HLA restriction, and the use of electroporated full length mRNA encoding full length parental proteins to ensure that any observed T cell responses are specific for antigens that are naturally processed and presented. CONCLUSIONS: This technique can serve as useful experimental approach to determine the induction or enhancement of specific responses to naturally processed and presented antigens on HLA class I molecules in peripheral blood or tumor infiltrating T cells.
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Apresentação de Antígeno , Células Apresentadoras de Antígenos , Antígenos de Neoplasias , Linfócitos B , Epitopos , Epitopos de Linfócito T , Linfócitos TRESUMO
The synthesis of a series of thiolated paclitaxel analogs is described as part of a novel nanomedicine program aimed at developing formulations of paclitaxel that will bind to gold nanoparticles for tumor targeted drug delivery. Preliminary evaluation of the new nanomedicine composed of 27 nm gold nanoparticles, tumor necrosis factor alpha (TNFα), thiolated polyethylene glycol (PEG-thiol), and one of several thiolated paclitaxel analogs is presented.
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Portadores de Fármacos/química , Portadores de Fármacos/síntese química , Ouro/química , Nanopartículas Metálicas/química , Paclitaxel/química , Paclitaxel/farmacologia , Animais , Soluções Tampão , Linhagem Celular Tumoral , Técnicas de Química Sintética , Liberação Controlada de Fármacos , Humanos , Camundongos , Modelos Moleculares , Paclitaxel/farmacocinética , Polietilenoglicóis/química , Conformação Proteica , Fator de Necrose Tumoral alfa/químicaRESUMO
Disparities in dental health care that characterize poor populations are well known. Children suffer disproportionately and most severely from dental diseases. Many countries have school-based dental therapist programs to meet children's primary oral health care needs. Although dental therapists in the United States face opposition from national and state dental associations, many state governments are considering funding the training and deployment of dental therapists to care for underserved populations. Dental therapists care for American Indians/Alaska Natives in Alaska, and Minnesota became the first state to legislate dental therapist training. Children should receive priority preference; therefore, the most effective and economical utilization of dental therapists will be as salaried employees in school-based programs, beginning in underserved rural areas and inner cities.
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Assistência Odontológica para Crianças/métodos , Acessibilidade aos Serviços de Saúde/organização & administração , Populações Vulneráveis , Alaska , Criança , Assistência Odontológica para Crianças/economia , Assistência Odontológica para Crianças/organização & administração , Disparidades em Assistência à Saúde/organização & administração , Humanos , Minnesota , Serviços de Saúde Escolar/organização & administração , Justiça Social , Estados Unidos/epidemiologiaRESUMO
OBJECTIVES: Tumor infiltrating neutrophils suppress T cell function, but whether neutrophils in circulation contribute to systemic immunosuppression is unclear. We aimed to study whether peripheral neutrophils that accumulate with tumor progression contribute to systemic immunosuppression, and if observed suppression of systemic anti-tumor immunity could be reversed with complete surgical tumor removal. MATERIALS AND METHODS: Syngeneic murine oral cancers were established in immunocompetent mice. Proteomic and functional immune assays were used to study plasma cytokine concentration, peripheral immune frequencies, and systemic anti-tumor immunity with and without complete primary tumor resection. RESULTS: Ly6G+ neutrophilic cells, but not other myeloid cell types, accumulated in the periphery of mice with progressing tumors. This accumulation positively associated with plasma G-CSF concentration. Circulating neutrophils were functionally immunosuppressive. Complete surgical tumor removal reversed the observed neutrophilia, with neutrophil frequencies returning to baseline in 21 days. Multiple independent functional assays revealed enhanced systemic anti-tumor immunity in mice following tumor resection compared to tumor-bearing mice, and the observed enhanced systemic immunity could be reproduced with selective neutrophil depletion. CONCLUSIONS: Complete primary tumor resection can reverse neutrophilia that develops during tumor progression and result in enhanced systemic anti-tumor immunity. Primary tumor removal relieves neutrophil-driven systemic immunosuppression and may itself contribute to the clinical benefit observed with neoadjuvant immunotherapy.
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Terapia de Imunossupressão , Proteômica , Animais , Camundongos , Linhagem Celular Tumoral , Imunoterapia , Tolerância Imunológica , Microambiente TumoralRESUMO
The United States faces a significant problem with access to oral health care, particularly for children. More than 50 countries have developed an alternative dental provider, a dental therapist, practicing in public, school-based programs, to address children's access to care. This delivery model has been demonstrated to improve access to care and oral health outcomes while providing quality care economically. We summarize elements of a recent major review of the global literature on the use of dental therapists, "A Review of the Global Literature on Dental Therapists: In the Context of the Movement to Add Dental Therapists to the Oral Health Workforce in the United States." We contrast the success of a school-based model of caring for children by dental therapists with that of the US model of dentists providing care for children in private practices.
Assuntos
Assistência Odontológica para Crianças/organização & administração , Técnicos em Prótese Dentária/organização & administração , Odontólogos/organização & administração , Serviços de Odontologia Escolar/organização & administração , Adolescente , Austrália , Canadá , Criança , Pré-Escolar , Assistência Odontológica para Crianças/economia , Assistência Odontológica para Crianças/normas , Acessibilidade aos Serviços de Saúde , Hong Kong , Humanos , Malásia , Nova Zelândia , Saúde Bucal , Qualidade da Assistência à Saúde , Singapura , Estados Unidos , Recursos HumanosRESUMO
OBJECTIVES: Biomarkers are needed to identify patients likely to respond to neoadjuvant immunotherapy (NIT) prior to receiving definitive treatment. MATERIALS AND METHODS: We hypothesized that expression of tumor cell HLA class I would correlate with pathologic response (PR) following NIT for primary untreated head and neck cancer. Multispectral immunofluorescence of pre- and post-treatment biopsy specimens from a neoadjuvant study of bintrafusp alfa, a dual TGF-ß and PD-L1 inhibitor, was performed. RESULTS: Discordant expression of tumor cell HLA class I and PD-L1 measured by multispectral immunofluorescence was observed with most positive tumor cells expressing HLA class I or PD-L1 but not both. Spatial analysis revealed colocalization between tumor parenchyma T cells and HLA class I positive tumors cells, but no clear colocalization between T cells and PD-L1 positive tumor cells. Greater pre-treatment tumor cell HLA class I expression, but not PD-L1 expression or tumor T cell infiltration, correlated with the development of a PR. Additionally, increased tumor cell HLA class I expression after NIT compared to before NIT correlated with development of a PR, whereas inconsistent changes in PD-L1 and T cell infiltration were observed after treatment in all patients. CONCLUSIONS: These data provide the rationale for the study of tumor cell HLA class I expression in larger prospective studies powered to determine the performance of biomarkers of PR in newly diagnosed HNSCC patients receiving NIT.
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Neoplasias de Cabeça e Pescoço , Antígenos de Histocompatibilidade Classe I , Humanos , Terapia Neoadjuvante , Estudos Prospectivos , Biomarcadores , Imunoterapia , Antígeno B7-H1/metabolismoRESUMO
BACKGROUND: Treatment of patients with newly diagnosed HPV-associated oropharyngeal squamous cell carcinoma (OPSCC) with neoadjuvant chemotherapy (NAC) results in a high rate of 5-year recurrence free survival with few patients requiring adjuvant treatment. We hypothesized that NAC enhances primary tumor HPV-specific T cell responses. METHODS: HPV-specific responses in tumor infiltrating lymphocytes (TILs) before and after NAC were determined using autologous co-culture assays. RESULTS: Greater HPV16-specific TIL responses, sometimes polyclonal, were observed after NAC compared to before in 8 of 10 patients (80%) with PCR-verified HPV16-positive tumors. A significant association was observed between net-negative change in HPV-specific TIL response and disease relapse (p = 0.04, Mann-Whitney test), whereas pathologic complete response at time of surgery did not correlate with recurrence. CONCLUSIONS: NAC induces HPV-specific tumor T cell responses in patients with newly diagnosed HPV-associated OPSCC; whereas lack of an increase following NAC may associate with risk of relapse.
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Neoplasias de Cabeça e Pescoço , Neoplasias Orofaríngeas , Infecções por Papillomavirus , Humanos , Linfócitos T , Prognóstico , Terapia Neoadjuvante/métodos , Infecções por Papillomavirus/complicações , Recidiva Local de Neoplasia , Neoplasias Orofaríngeas/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/complicações , Neoplasias de Cabeça e Pescoço/complicaçõesRESUMO
Neoadjuvant immunotherapies (NITs) have led to clinical benefits in several cancers. Characterization of the molecular mechanisms underlying responses to NIT may lead to improved treatment strategies. Here we show that exhausted, tumor-infiltrating CD8+ T (Tex) cells display local and systemic responses to concurrent neoadjuvant TGF-ß and PD-L1 blockade. NIT induces a significant and selective increase in circulating Tex cells associated with reduced intratumoral expression of the tissue-retention marker CD103. TGF-ß-driven CD103 expression on CD8+ T cells is reversed following TGF-ß neutralization in vitro, implicating TGF-ß in T cell tissue retention and impaired systemic immunity. Transcriptional changes implicate T cell receptor signaling and glutamine metabolism as important determinants of enhanced or reduced Tex treatment response, respectively. Our analysis illustrates physiological and metabolic changes underlying T cell responses to NIT, highlighting the interplay between immunosuppression, tissue retention, and systemic anti-tumor immunity and suggest antagonism of T cell tissue retention as a promising neoadjuvant treatment strategy.
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Linfócitos T CD8-Positivos , Neoplasias de Cabeça e Pescoço , Humanos , Terapia Neoadjuvante , Neoplasias de Cabeça e Pescoço/terapia , Neoplasias de Cabeça e Pescoço/metabolismo , Imunoterapia , Fator de Crescimento Transformador beta/metabolismo , Adaptação Fisiológica , Linfócitos do Interstício TumoralRESUMO
Recurrent respiratory papillomatosis (RRP) is a rare, debilitating neoplastic disorder caused by chronic infection with human papillomavirus (HPV) type 6 or 11 and characterized by growth of papillomas in the upper aerodigestive tract. There is no approved medical therapy, and patients require repeated debulking procedures to maintain voice and airway function. PRGN-2012 is a gorilla adenovirus immune-therapeutic capable of enhancing HPV 6/11-specific T cell immunity. This first-in-human, phase 1 study (NCT04724980) of adjuvant PRGN-2012 treatment in adult patients with severe, aggressive RRP demonstrates the overall safety and clinically meaningful benefit observed with PRGN-2012, with a 50% complete response rate in patients treated at the highest dose. Responders demonstrate greater expansion of peripheral HPV-specific T cells compared with nonresponders. Additional correlative studies identify an association between reduced baseline papilloma HPV gene expression, greater interferon responses and expression of CXCL9 and CXCL10, and greater papilloma T cell infiltration in responders. Conversely, nonresponders were characterized by greater HPV and CXCL8 gene expression, increased neutrophilic cell infiltration, and reduced T cell papilloma infiltration. These results suggest that papilloma HPV gene expression may regulate interferon signaling and chemokine expression profiles within the tumor microenvironment that cooperate to govern clinical response to therapeutic HPV vaccination in patients with respiratory papillomatosis.
Assuntos
Papiloma , Infecções por Papillomavirus , Infecções Respiratórias , Adulto , Humanos , Infecções por Papillomavirus/terapia , Infecções por Papillomavirus/patologia , Microambiente Tumoral , Infecções Respiratórias/terapia , Interferons , Papiloma/terapia , Papiloma/patologia , VacinaçãoRESUMO
BACKGROUND: Immune checkpoint blockade can provide clinical benefit for patients with advanced cancer. Here, we report durable disease control over many years following PD-L1 blockade through induction of a viral antigen-specific T cell response in an adult patient with recurrent respiratory papillomatosis. METHODS: Antigen-specific T cell response assays, single cell RNA-sequencing, and RNA-scope was used to study clinical tissues. RESULTS: An HPV6 E2-specific T cell clone restricted to HLA-B*55, present at low frequency in the pre-treatment papilloma, significantly expanded after six doses of PD-L1 blockade and remained present and functional at the site of initial response in the larynx as a tissue resident memory T cell for 4 years. An associated reduction in E2 target gene was observed following treatment. CONCLUSIONS: Although demonstrated in a single exceptional responder, these results highlight that immune checkpoint blockade may induce durable, viral antigen-specific immunity of sufficient magnitude to control disease in patients with nonmalignant disorders.
Assuntos
Antígeno B7-H1 , Papiloma , Adulto , Antígenos Virais , Humanos , Inibidores de Checkpoint Imunológico , Infecções por Papillomavirus , RNA , Infecções RespiratóriasRESUMO
BACKGROUNDHead and neck squamous cell carcinoma not associated with HPV (HPV-unrelated HNSCC) is associated with a high rate of recurrence and poor survival.METHODSWe conducted a clinical trial in 14 patients with newly diagnosed HPV-unrelated HNSCC to evaluate the safety and efficacy of neoadjuvant bintrafusp alfa, a bifunctional fusion protein that blocks programmed death ligand 1 (PD-L1) and neutralizes TGF-ß.RESULTSBintrafusp alfa was well tolerated, and no treatment-associated surgical delays or complications occurred. Objective pathologic responses (PRs) were observed, and 12 of the 14 (86%) patients were alive and disease free at 1 year. Alterations in Treg infiltration and spatial distribution relative to proliferating CD8+ T cells indicated a reversal of Treg immunosuppression in the primary tumor. Detection of neoepitope-specific tumor T cell responses, but not virus-specific responses, correlated with the development of a PR. Detection of neoepitope-specific responses and PRs in tumors was not correlated with genomic features or tumor antigenicity but was associated with reduced pretreatment myeloid cell tumor infiltration. These results indicate that dual PD-L1 and TGF-ß blockade can safely enhance tumor antigen-specific immunity and highlight the feasibility of multimechanism neoadjuvant immunotherapy for patients with HPV-unrelated HNSCC.CONCLUSIONOur studies provide insight into the ability of neoadjuvant immunotherapy to induce polyclonal neoadjuvant-specific T cell responses in tumors and suggest that features of the tumor microenvironment, such as myeloid cell infiltration, may be a major determinant of enhanced antitumor immunity following such treatment.TRIAL REGISTRATIONClinicalTrials.gov NCT04247282.FUNDINGThis work was funded by the Center for Cancer Research, the NCI, and the Intramural Research Program of the NIDCD, NIH. Bintrafusp alfa was provided by the health care business of Merck KGaA (Darmstadt, Germany), through a Cooperative Research and Development Agreement with the NCI. Additional funding was provided by ImmunityBio through a Cooperative Research and Development Agreement with the NIDCD.
Assuntos
Neoplasias de Cabeça e Pescoço , Infecções por Papillomavirus , Antígenos de Neoplasias/uso terapêutico , Antígeno B7-H1 , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Humanos , Terapia Neoadjuvante , Infecções por Papillomavirus/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/terapia , Fator de Crescimento Transformador beta , Microambiente TumoralRESUMO
Dental therapists provide preventive, restorative, and minor surgical treatment, mostly for children in government-sponsored health programs, in more than 53 countries. Their quality of care and acceptance by the public and dental profession has been well-documented. Since 2005, they have been effectively serving native Alaskans in remote communities. Not only do dental therapists provide basic dental care to underserved populations, they enable associated dentists to practice at a higher level of proficiency and efficiency.
Assuntos
Auxiliares de Odontologia/estatística & dados numéricos , Assistência Odontológica para Crianças , Odontologia em Saúde Pública , Idoso , Alaska , Austrália , Canadá , Criança , Auxiliares de Odontologia/educação , Assistência Odontológica para Idosos , Fiji , Acessibilidade aos Serviços de Saúde , Humanos , Internacionalidade , Países Baixos , Nova Zelândia , Odontologia Estatal , Reino Unido , Recursos HumanosRESUMO
Recurrent respiratory papillomatosis (RRP) is a debilitating neoplastic disorder of the upper aerodigestive tract caused by chronic infection with low-risk human papillomavirus types 6 or 11. Patients with severe RRP can require hundreds of lifetime surgeries to control their disease and pulmonary papillomatosis can be fatal. Here we report the comprehensive genomic and transcriptomic characterization of respiratory papillomas. We discovered and characterized distinct subtypes with transcriptional resemblance to either a basal or differentiated cell state that associate with disease aggressiveness and differ in key molecular, immune and APOBEC mutagenesis profiles. Through integrated comparison with high-risk HPV-associated head and neck squamous cell carcinoma, our analysis revealed divergent molecular and immune papilloma subtypes that form independent of underlying genomic alterations. Cumulatively our results support the development of dysregulated cellular proliferation and suppressed anti-viral immunity through distinct programs of squamous cell differentiation and associated expression of low-risk HPV genes. These analyses provide insight into the pathogenesis of respiratory papillomas and provide a foundation for the development of therapeutic strategies.
Assuntos
Genoma , Papillomavirus Humano 11/genética , Papillomavirus Humano 6/genética , Infecções por Papillomavirus/virologia , Infecções Respiratórias/virologia , Transcriptoma , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
BACKGROUND: Recurrent respiratory papillomatosis (RRP) is a human papillomavirus (HPV) driven neoplastic disorder of the upper aerodigestive tract that causes significant morbidity and can lead to fatal airway obstruction. Prior clinical study demonstrated clinical benefit with the programmed death-ligand 1 (PD-L1) monoclonal antibody avelumab. Bintrafusp alpha is a bifunctional inhibitor of PD-L1 and transforming growth factor-beta (TGF-b) that has shown clinical activity in several cancer types. METHODS: We conducted a phase II clinical trial evaluating bintrafusp alpha in adults with RRP. Papilloma samples before and after treatment with bintrafusp alpha were assessed for correlates of response with multiplex immunofluorescence as well as immunological and genomic analyses. Post hoc analyses of papilloma samples before and after treatment with avelumab were assessed for comparison. RESULTS: Dual PD-L1/TGF-b inhibition failed to abrogate papilloma growth in most subjects and increased the frequency of clinically indicated interventions after treatment in four of eight subjects based on each subject's own historical control. TGF-b neutralization consistently decreased pSMAD3 and p21 and increased Ki67 expression within the basal layers of papillomas, indicating that TGF-b restrained proliferation. These alterations were not observed in papillomas treated with PD-L1 blockade alone. Dual PD-L1/TGF-b inhibition did not enhance anti-HPV immunity within papillomas beyond that observed with PD-L1 blockade. Genomic alterations in TGF-b superfamily genes were infrequent in papillomas and normal mucosa but present in a significant fraction of head and neck carcinomas. CONCLUSIONS: Intact TGF-b signaling restrains proliferation within papillomas, and the use of clinical agents that abrogate this pathway should be avoided in patients with RRP. TRIAL REGISTRATION NUMBERS: NCT03707587 and NCT02859454.
Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Inibidores de Checkpoint Imunológico/uso terapêutico , Imunoterapia/métodos , Infecções por Papillomavirus/tratamento farmacológico , Infecções Respiratórias/tratamento farmacológico , Fator de Crescimento Transformador beta/antagonistas & inibidores , Animais , Anticorpos Monoclonais/uso terapêutico , Feminino , Humanos , Fatores Imunológicos/uso terapêutico , Camundongos , Células NIH 3T3 , Papiloma/tratamento farmacológico , Microambiente Tumoral/imunologiaRESUMO
BACKGROUND: As heterogeneous tumors develop in the face of intact immunity, tumor cells harboring genomic or expression defects that favor evasion from T-cell detection or elimination are selected. For patients with such tumors, T cell-based immunotherapy alone infrequently results in durable tumor control. METHODS: Here, we developed experimental models to study mechanisms of T-cell escape and demonstrated that resistance to T-cell killing can be overcome by the addition of natural killer (NK) cells engineered to express a chimeric antigen receptor (CAR) targeting programmed death ligand-1 (PD-L1). RESULTS: In engineered models of tumor heterogeneity, PD-L1 CAR-engineered NK cells (PD-L1 t-haNKs) prevented the clonal selection of T cell-resistant tumor cells observed with T-cell treatment alone in multiple models. Treatment of heterogenous cancer cell populations with T cells resulted in interferon gamma (IFN-γ) release and subsequent upregulation of PD-L1 on tumor cells that escaped T-cell killing through defects in antigen processing and presentation, priming escape cell populations for PD-L1 dependent killing by PD-L1 t-haNKs in vitro and in vivo. CONCLUSIONS: These results describe the underlying mechanisms governing synergistic antitumor activity between T cell-based immunotherapy that results in IFN-γ production, upregulation of PD-L1 on T-cell escape cells, and the use of PD-L1 CAR-engineered NK cells to target and eliminate resistant tumor cell populations.
Assuntos
Edição de Genes , Neoplasias de Cabeça e Pescoço/terapia , Imunoterapia Adotiva , Células Matadoras Naturais/transplante , Linfócitos do Interstício Tumoral/imunologia , Receptores de Antígenos Quiméricos/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/terapia , Linfócitos T/transplante , Evasão Tumoral , Animais , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Sistemas CRISPR-Cas , Linhagem Celular Tumoral , Bases de Dados Genéticas , Antígenos HLA/metabolismo , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/imunologia , Neoplasias de Cabeça e Pescoço/metabolismo , Humanos , Interferon gama/metabolismo , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Ativação Linfocitária , Linfócitos do Interstício Tumoral/metabolismo , Camundongos Endogâmicos NOD , Camundongos SCID , Receptores de Antígenos Quiméricos/imunologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/imunologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Carga Tumoral , Microambiente Tumoral , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
PURPOSE: Gefitinib targeting of the epidermal growth factor receptor (EGFR) has shown limited activity in clinical trials of head and neck squamous cell carcinoma (HNSCC). To investigate the underlying molecular mechanism, the proteomic signatures and responses of EGFR and downstream signals have been studied in a panel of HNSCC cell lines and tumor specimens pre- and post-gefitinib treatment. EXPERIMENTAL DESIGN: The IC(50) of gefitinib for HNSCC cell lines were determined using 3-(4,5-dmethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide proliferation assay. The effects of gefitinib on activation of EGFR and downstream signaling molecules were determined by Western blot, ELISA, and reverse-phase protein microarray (RPMA). The biomarkers involved in the signaling pathways were examined in HNSCC tumor specimens from patients in a phase I gefitinib trial. RESULTS: In vitro, gefitinib inhibited cell proliferation with differing IC(50), and suppressed activation of EGFR and downstream signaling molecules protein kinase B (AKT), extracellular signal-regulated kinase 1/2, signal transducer and activator of transcription 3 (STAT3), and nuclear factor kappaB. The drug sensitivity was statistically correlated with activation of phosphorylated AKT (p-AKT) and phosphorylated STAT3 (p-STAT3) detected by ELISA, and consistent with results measured by RPMA. In patient samples, a broad suppression of activation of EGFR and downstream signaling molecules was observed in a molecular responder patient, in contrast to a lack of inhibition or increased activation of biomarkers in different pathways in nonresponder patients. CONCLUSIONS: Gefitinib sensitivity is correlated with p-AKT and p-STAT3 activation in HNSCC cell lines and tumor specimens. p-AKT and p-STAT3 could serve as potentially useful biomarkers and drug targets for further development of novel therapeutic agents for HNSCC.
Assuntos
Antineoplásicos/farmacologia , Carcinoma de Células Escamosas/metabolismo , Receptores ErbB/antagonistas & inibidores , Neoplasias de Cabeça e Pescoço/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Quinazolinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/análise , Western Blotting , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/enzimologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Ensaios Clínicos Fase I como Assunto , Ensaio de Imunoadsorção Enzimática , Fator de Crescimento Epidérmico/antagonistas & inibidores , Receptores ErbB/metabolismo , Gefitinibe , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/enzimologia , Humanos , Concentração Inibidora 50 , NF-kappa B/antagonistas & inibidores , Fosforilação , Análise Serial de Proteínas , Inibidores de Proteínas Quinases/uso terapêutico , Proteômica , Quinazolinas/uso terapêuticoRESUMO
PURPOSE: Natural killer (NK)-cell-based immunotherapy may overcome obstacles to effective T-cell-based immunotherapy such as the presence of genomic alterations in IFN response genes and antigen presentation machinery. All immunotherapy approaches may be abrogated by the presence of an immunosuppressive tumor microenvironment present in many solid tumor types, including head and neck squamous cell carcinoma (HNSCC). Here, we studied the role of myeloid-derived suppressor cells (MDSC) in suppressing NK-cell function in HNSCC. EXPERIMENTAL DESIGN: The ability of peripheral and tumor-infiltrating MDSC from mice bearing murine oral cancer 2 (MOC2) non-T-cell-inflamed tumors and from patients with HNSCC to suppress NK-cell function was studied with real-time impedance and ELISpot assays. The therapeutic efficacy of SX-682, a small-molecule inhibitor of CXCR1 and CXCR2, was assessed in combination with adoptively transferred NK cells. RESULTS: Mice bearing MOC2 tumors pathologically accumulate peripheral CXCR2+ neutrophilic-MDSC (PMN-MDSC) that traffic into tumors and suppress NK-cell function through TGFß and production of H2O2. Inhibition of MDSC trafficking with orally bioavailable SX-682 significantly abrogated tumor MDSC accumulation and enhanced the tumor infiltration, activation, and therapeutic efficacy of adoptively transferred murine NK cells. Patients with HNSCC harbor significant levels of circulating and tumor-infiltrating CXCR1/2+ CD15+ PMN-MDSC and CD14+ monocytic-MDSC. Tumor MDSC exhibited greater immunosuppression than those in circulation. HNSCC tumor MDSC immunosuppression was mediated by multiple, independent, cell-specific mechanisms including TGFß and nitric oxide. CONCLUSIONS: The clinical study of CXCR1/2 inhibitors in combination with adoptively transferred NK cells is warranted.
Assuntos
Antineoplásicos Imunológicos/farmacologia , Neoplasias de Cabeça e Pescoço/terapia , Células Matadoras Naturais/imunologia , Neoplasias Bucais/terapia , Células Supressoras Mieloides/metabolismo , Receptores de Interleucina-8A/antagonistas & inibidores , Receptores de Interleucina-8B/antagonistas & inibidores , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Neoplasias de Cabeça e Pescoço/imunologia , Neoplasias de Cabeça e Pescoço/metabolismo , Humanos , Imunoterapia/métodos , Células Matadoras Naturais/efeitos dos fármacos , Leucócitos Mononucleares , Camundongos , Camundongos Endogâmicos C57BL , Neoplasias Bucais/imunologia , Neoplasias Bucais/metabolismo , Células Supressoras Mieloides/efeitos dos fármacos , Células Supressoras Mieloides/imunologia , Fator de Crescimento Transformador beta/imunologia , Fator de Crescimento Transformador beta/metabolismo , Microambiente TumoralRESUMO
Failed T cell-based immunotherapies in the presence of genomic alterations in antigen presentations pathways may be overcome by NK cell-based immunotherapy. This approach may still be limited by the presence of immunosuppressive myeloid populations. Here, we demonstrate that NK cells (haNKs) engineered to express a PD-L1 chimeric antigen receptor (CAR) haNKs killed a panel of human and murine head and neck cancer cells at low effector-to-target ratios in a PD-L1-dependent fashion. Treatment of syngeneic tumors resulted in CD8 and PD-L1-dependent tumor rejection or growth inhibition and a reduction in myeloid cells endogenously expressing high levels of PD-L1. Treatment of xenograft tumors resulted in PD-L1-dependent tumor growth inhibition. PD-L1 CAR haNKs reduced levels of macrophages and other myeloid cells endogenously expressing high PD-L1 in peripheral blood from patients with head and neck cancer. The clinical study of PD-L1 CAR haNKs is warranted.