RESUMO
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
Recruitment of myeloid-derived suppressor cells (MDSCs) into tumors induces local immunosuppression in carcinomas. Here, we assessed whether SX-682, an orally bioavailable small-molecule inhibitor of CXCR1 and CXCR2, could block tumor MDSC recruitment and enhance T cell activation and antitumor immunity following multiple forms of immunotherapy. CXCR2+ neutrophilic MDSCs (PMN-MDSCs) were the most abundant myeloid cell subset within oral and lung syngeneic carcinomas. PMN-MDSCs demonstrated greater suppression of tumor-infiltrating lymphocyte killing of targets compared with macrophages. SX-682 significantly inhibited trafficking of PMN-MDSCs without altering CXCR2 ligand expression. Trafficking of CXCR1+ macrophages was unaltered, possibly due to coexpression of CSF1R. Reduced PMN-MDSC tumor infiltration correlated with enhanced accumulation of endogenous or adoptively transferred T cells. Accordingly, tumor growth inhibition or the rate of established tumor rejection following programed death-axis (PD-axis) immune checkpoint blockade or adoptive cell transfer of engineered T cells was enhanced in combination with SX-682. Despite CXCR1/2 expression on tumor cells, SX-682 appeared to have little direct antitumor effect on these carcinoma models. These data suggest that tumor-infiltrating CXCR2+ PMN-MDSCs may prevent optimal responses following both PD-axis immune checkpoint blockade and adoptive T cell transfer therapy. Abrogation of PMN-MDSC trafficking with SX-682 enhances T cell-based immunotherapeutic efficacy and may be of benefit to patients with MDSC-infiltrated cancers.
Assuntos
Antineoplásicos Imunológicos/farmacologia , Carcinoma/terapia , Movimento Celular/efeitos dos fármacos , Neoplasias Pulmonares/terapia , Neoplasias Bucais/terapia , Células Supressoras Mieloides/efeitos dos fármacos , Animais , Antineoplásicos Imunológicos/uso terapêutico , Carcinoma/imunologia , Carcinoma/patologia , Linhagem Celular Tumoral/transplante , Movimento Celular/imunologia , Terapia Combinada/métodos , Modelos Animais de Doenças , Humanos , Tolerância Imunológica/efeitos dos fármacos , Imunoterapia Adotiva/métodos , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Linfócitos do Interstício Tumoral/imunologia , Camundongos , Neoplasias Bucais/imunologia , Neoplasias Bucais/patologia , Células Supressoras Mieloides/imunologia , Células Supressoras Mieloides/metabolismo , Neutrófilos/imunologia , Neutrófilos/metabolismo , Receptores de Interleucina-8A/antagonistas & inibidores , Receptores de Interleucina-8A/imunologia , Receptores de Interleucina-8A/metabolismo , Receptores de Interleucina-8B/antagonistas & inibidores , Receptores de Interleucina-8B/imunologia , Receptores de Interleucina-8B/metabolismo , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/transplante , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologiaAssuntos
Coroideremia/metabolismo , Coroideremia/patologia , Transporte Proteico/fisiologia , Doenças Retinianas/metabolismo , Doenças Retinianas/patologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Adolescente , Biomarcadores/sangue , Quimiocina CCL2/sangue , Coroideremia/genética , Proteínas do Olho/sangue , Saúde da Família , Humanos , Masculino , Fatores de Crescimento Neural/sangue , Fagocitose/fisiologia , Fenótipo , Valor Preditivo dos Testes , Doenças Retinianas/genética , Serpinas/sangue , Índice de Gravidade de Doença , Irmãos , Fator A de Crescimento do Endotélio Vascular/sangueRESUMO
Checkpoint inhibitors are relatively inefficacious in head and neck cancers, despite an abundance of genetic alterations and a T-cell-inflamed phenotype. One significant barrier to efficacy may be the recruitment of myeloid-derived suppressor cells (MDSC) into the tumor microenvironment. Here we demonstrate functional inhibition of MDSC with IPI-145, an inhibitor of PI3Kδ and PI3Kγ isoforms, which enhances responses to PD-L1 blockade. Combination therapy induced CD8+ T lymphocyte-dependent primary tumor growth delay and prolonged survival only in T-cell-inflamed tumor models of head and neck cancers. However, higher doses of IPI-145 reversed the observed enhancement of anti-PD-L1 efficacy due to off-target suppression of the activity of tumor-infiltrating T lymphocytes. Together, our results offer a preclinical proof of concept for the low-dose use of isoform-specific PI3Kδ/γ inhibitors to suppress MDSC to enhance responses to immune checkpoint blockade. Cancer Res; 77(10); 2607-19. ©2017 AACR.