Co-opting STING signaling for NK-cell based immunotherapies in thoracic malignancies

Abstract

Thoracic cancers, including small cell lung cancer (SCLC) and malignant pleural mesothelioma (MPM), are aggressive forms of lung cancer. In contrast to non-small cell lung cancer, their treatment is mainly based on chemotherapy with marginal benefit from immunotherapy, and the overall survival rate is low. Thus, novel treatment strategies are necessary for better clinical outcomes. Adoptive immune cell therapy and genetically engineered chimeric antigen receptor (CAR) lymphocytes have shown promising clinical implications in multiple cancer types and proved successful in patients with hematologic malignancies. Major histocompatibility complex (MHC) class I protein is essential in antigen presentation. Low MHC class I expression in SCLC nominates a potential therapeutic target for NK cell therapy, but heterogeneity may complicate matters. At the same time, MPM upregulates mesothelin, a surface protein that represents an antigen target for CAR cell therapies. However, CAR-NK cell infiltration and expansion have proven challenging in solid tumors due to insufficient immune cell homing in the tumor microenvironment (TME). Consequently, the success rate for cell therapies in solid tumors remains low. We performed functional ex vivo studies of NK cell therapy in SCLC and MPM. SCLC sensitivity to NK cell-mediated killing was measured in both 2-Dimensional (2D)-culture and 3D- microfluidic culture systems. Furthermore, more sophisticated 3D microphysiological systems were developed to mimic the physiological interactions within the TME better. We also observed that STING agonists enhanced NK cell migration and killing, improving therapeutic activity in MPM cell lines. These studies identified the CXCR3-CXCL10 receptor-chemokine axis as a promising candidate for increasing NK cell trafficking into the TME and enhancing antitumor immunity in intractable thoracic cancers. This work reveals that ex vivo human tumor models can facilitate the study of innate and cellular immune therapies, characterizing the heterogeneity of susceptibility to NK cell therapy in SCLC and identifying STING agonism as an effective strategy to prime NK cell therapy in MPM.