Only a subpopulation of non-small cell lung cancer (NSCLC) patients responds to immunotherapies, highlighting the urgent need to develop therapeutic strategies to improve patient outcome. We develop a chemical positive modulator (HEI3090) of the purinergic P2RX7 receptor that potentiates αPD-1 treatment to effectively control the growth of lung tumors in transplantable and oncogene-induced mouse models and triggers long lasting antitumor immune responses. Mechanistically, the molecule stimulates dendritic P2RX7-expressing cells to generate IL-18 which leads to the production of IFN-γ by Natural Killer and CD4⁺ T cells within tumors. Combined with immune checkpoint inhibitor, the molecule induces a complete tumor regression in 80% of LLC tumor-bearing mice. Cured mice are also protected against tumor re-challenge due to a CD8-dependent protective response. Hence, combination treatment of small-molecule P2RX7 activator followed by immune checkpoint inhibitor represents a strategy that may be active against NSCLC.

Cancer is the leading cause of death worldwide despite the variety of treatments that are currently used. This is due to an innate or acquired resistance to therapy that encourages the discovery of novel therapeutic strategies to overcome the resistance. This review will focus on the role of the purinergic receptor P2RX7 in the control of tumor growth, through its ability to modulate antitumor immunity by releasing IL-18. In particular, we describe how the ATP-induced receptor activities (cationic exchange, large pore opening and NLRP3 inflammasome activation) modulate immune cell functions. Furthermore, we recapitulate our current knowledge of the production of IL-18 downstream of P2RX7 activation and how IL-18 controls the fate of tumor growth. Finally, the potential of targeting the P2RX7/IL-18 pathway in combination with classical immunotherapies to fight cancer is discussed.

Telomeric repeat-binding factor 2 (TRF2) is a subunit of the shelterin protein complex, which binds to and protects telomeres from unwanted DNA damage response (DDR) activation. TRF2 expression plays a pivotal role in aging and cancer, being downregulated during cellular senescence and overexpressed during oncogenesis. Cancers overexpressing TRF2 often exhibit a poor prognosis. In cancer cells, TRF2 plays multiple functions, including telomere protection and non-cell autonomous roles, promoting neo-angiogenesis and immunosuppression. We present here an original screening strategy, which enables identification of small molecules that decrease or increase TRF2 expression. By screening a small library of Food and Drug Agency (FDA)-approved drugs, we identified two molecules (AR-A014418 and alexidine·2HCl) that impaired tumor growth, neo-angiogenesis and immunosuppression by downregulating TRF2 expression in a mouse xenograft model. These results support the chemotherapeutic strategy of downregulating TRF2 expression to treat aggressive human tumors and validate this cell-based assay capable of screening for potential anti-cancer and anti-aging molecules by modulating TRF2 expression levels.

The aim of this study was to assess the potential value of circulating active and inactive IL-18 levels in distinguishing pseudo and true tumor progression among NSCLC patients receiving immune checkpoint inhibitor treatments (ICIs). Methods: This ancillary study includes 195 patients with metastatic non-small-cell lung cancer (NSCLC) treated with ICI in monotherapy, either pembrolizumab or nivolumab. Plasmatic levels of IL-18-related compounds, comprising the inhibitor IL-18 binding protein (IL-18BP), the inactive IL-18 (corresponding to IL-18/IL-18BP complex), and the active free IL-18, were assayed by ELISA. Objective tumoral response was analyzed by ¹⁸FDG PET-CT at baseline, 7 weeks, and 3 months post treatment induction, using PERCIST criteria. Results: Plasmatic IL-18BP and total IL-18 levels are increased at baseline in NSCLC patients compared with healthy controls, whereas IL-18/IL-18BP complexes are decreased, and free IL-18 levels remain unchanged. Neither of the IL-18-related compounds allowed to discriminate ICI responding to nonresponding patients. However, inactive IL-18 levels allowed to discriminate patients with a first tumor progression, assessed after 7 weeks of treatment, with worse overall survival. In addition, we showed that neutrophil concentration is also a predictive indicator of patients’ outcomes with OS (HR = 2.6, p = 0.0001) and PFS (HR = 2.2, p = 0.001). Conclusions: Plasmatic levels of inactive IL-18, combined with circulating neutrophil concentrations, can effectively distinguish ICI nonresponding patients with better overall survival (OS), potentially guiding rapid decisions for therapeutic intensification.

Lung cancer is the most common cancer worldwide. Despite recent therapeutic advances, including targeted therapies and immune checkpoint inhibitors, the disease progresses in almost all advanced lung cancers and in up to 50% of early-stage cancers. The purpose of this review is to discuss whether purinergic checkpoints (CD39, CD73, P2RX7, and ADORs), which shape the immune response in the tumor microenvironment, may represent novel therapeutic targets to combat progression of non-small cell lung cancer by enhancing the antitumor immune response.