Targeting CD70 in combination with chemotherapy to enhance the anti-tumor immune effects in non-small cell lung cancer

Abstract

ABSTRACT Despite the recent emergence of immune checkpoint inhibitors, clinical outcomes of metastatic NSCLC patients remain poor, pointing out the unmet need to develop novel therapies to enhance the anti-tumor immune response in NSCLC. In this regard, aberrant expression of the immune checkpoint molecule CD70 has been reported on many cancer types, including NSCLC. In this study, the cytotoxic and immune stimulatory potential of an antibody-based anti-CD70 (aCD70) therapy was explored as single agent and in combination with docetaxel and cisplatin in NSCLC in vitro and in vivo. Anti-CD70 therapy resulted in NK-mediated killing of NSCLC cells and increased production of pro-inflammatory cytokines by NK cells in vitro. The combination of chemotherapy and anti-CD70 therapy further enhanced NSCLC cell killing. Moreover, in vivo findings showed that the sequential treatment of chemo-immunotherapy resulted in a significant improved survival and delayed tumor growth compared to single agents in Lewis Lung carcinoma-bearing mice. The immunogenic potential of the chemotherapeutic regimen was further highlighted by increased numbers of dendritic cells in the tumor-draining lymph nodes in these tumor-bearing mice after treatment. The sequential combination therapy resulted in enhanced intratumoral infiltration of both T and NK cells, as well as an increase in the ratio of CD8+ T cells over Tregs. The superior effect of the sequential combination therapy on survival was further confirmed in a NCI-H1975-bearing humanized IL15-NSG-CD34+ mouse model. These novel preclinical data demonstrate the potential of combining chemotherapy and aCD70 therapy to enhance anti-tumor immune responses in NSCLC patients.