Efficacy and safety of anti-PD-1/PD-L1-based dual immunotherapies versus PD-1/PD-L1 inhibitor alone in patients with advanced solid tumor: a systematic review and meta-analysis.

INTRODUCTION: Numerous randomized controlled trials (RCTs) have investigated PD-1/PD-L1 inhibitor-based combination therapies. The debate surrounding the potential additive clinical benefits of combination of two immune-oncology (IO) therapies for cancer patients persists. METHODS: Both published and grey sources of randomized clinical trials that compared anti-PD-1/PD-L1-based immunotherapy combinations with monotherapy in patients with advanced or metastatic solid tumors were encompassed. The primary outcome was progression-free survival (PFS), and secondary outcomes included objective response rate (ORR), overall survival (OS) and treatment-related adverse events (TRAEs). RESULTS: Our analysis encompassed 31 studies comprising 10,341 patients, which covered 12 distinct immune-oncology combination regimens. Across all patients, the immunotherapy combinations exhibited the capability to enhance the ORR (OR = 1.23 [95% CI 1.13-1.34]) and extend PFS (HR = 0.91 [95% CI 0.87-0.95]). However, the observed enhancement in OS (HR = 0.96 [95% CI 0.91-1.01]) was of no significance. Greater benefits in terms of PFS (HR = 0.82 [95% CI 0.72 to 0.93]) and OS (HR = 0.85 [95% CI 0.73 to 0.99]) may be particularly pronounced in cases where PD-L1 expression is negative. Notably, despite a heightened risk of any-grade TRAEs (OR = 1.72 [95% CI 1.40-2.11]) and grade greater than or equal to 3 TRAEs (OR = 2.01 [95% CI 1.67-2.43]), toxicity was generally manageable. CONCLUSIONS: This study suggests that incorporating an additional immunotherapy agent with PD-1/PD-L1 inhibitors can elevate the response rate and reduce the risk of disease progression, all while maintaining manageable toxicity. However, there remains a challenge in translating these primary clinical benefits into extended overall survival.

A novel oral TLR7 agonist orchestrates immune response and synergizes with PD-L1 blockade via type I IFN pathway in lung cancer.

Despite the groundbreaking impact of immune checkpoint blockade (ICB), response rates in non-small cell lung cancer remain modest, particularly in immune-excluded or immune-desert microenvironments. Toll-like receptor 7 (TLR7) emerges as a latent target bridging innate and adaptive immunity, offering a promising avenue for combination therapies to augment ICB efficacy. Here, we explored the anti-tumor activity of the novel oral TLR7 agonist TQ-A3334 and its potential to enhance anti-programmed death ligand 1 (PD-L1) therapy through a combination strategy in a syngeneic murine lung cancer model. Oral administration of TQ-A3334 significantly alleviated tumor burden in C57BL/6J mice, modulated by type I interferon (IFN), and exhibited low toxicity. This therapy elicited activation of both innate and adaptive immune cells in tumor tissue, particularly increasing the abundance of CD8+ TILs through type I IFN pathway and subsequent CXCL10 expression. In vitro examinations validated that IFN-α-stimulated tumor cells exhibited increased secretion of CXCL10, conducive to the promoted trafficking of CD8+ T cells. Furthermore, combining TQ-A3334 with anti-PD-L1 treatment exceeded tumor control, with a further increase in CD8+ TIL frequency compared to monotherapy. These findings suggest that TQ-A3334 can mobilize innate immunity and promote T cell recruitment into the tumor microenvironment; a combination of TQ-A3334 and anti-PD-L1 antibodies can intensify the sensitivity of tumors to anti-PD-L1 therapy, which demonstrates significant potential for treating poorly immune-infiltrated lung cancer.

NAT10-mediated upregulation of GAS5 facilitates immune cell infiltration in non-small cell lung cancer via the MYBBP1A-p53/IRF1/type I interferon signaling axis.

Interactions of tumor cells with immune cells in the tumor microenvironment play an important role during malignancy progression. We previously identified that GAS5 inhibited tumor development by suppressing proliferation of tumor cells in non-small cell lung cancer (NSCLC). Herein, we discovered a tumor-suppressing role for tumor cell-derived GAS5 in regulating tumor microenvironment. GAS5 positively coordinated with the infiltration of macrophages and T cells in NSCLC clinically, and overexpression of GAS5 promoted macrophages and T cells recruitment both in vitro and in vivo. Mechanistically, GAS5 stabilized p53 by directly binding to MYBBP1A and facilitating MYBBP1A-p53 interaction, and enhanced p53-mediated transcription of IRF1, which activated type I interferon signaling and increased the production of downstream CXCL10 and CCL5. We also found that activation of type I interferon signaling was associated with better immunotherapy efficacy in NSCLC. Furthermore, the stability of GAS5 was regulated by NAT10, the key enzyme responsible for N4-acetylcytidine (ac4C) modification, which bound to GAS5 and mediated its ac4C modification. Collectively, tumor cell-derived GAS5 could activate type I interferon signaling via the MYBBP1A-p53/IRF1 axis, promoting immune cell infiltration and potentially correlating with immunotherapy efficacy, which suppressed NSCLC progression. Our results suggested GAS5 as a promising predictive marker and potential therapeutic target for combination therapy in NSCLC. A schematic diagram demonstrating the regulatory effect of GAS5 on immune cell infiltration by activating type I interferon signaling via MYBBP1A-p53/IRF1 axis in non-small cell lung cancer. IFN, interferon.

Hippocampal microglia CD40 mediates NPSLE cognitive dysfunction in mice.

Neuropsychiatric systemic lupus erythematosus (NPSLE) is the most serious and complicated clinical manifestation of lupus erythematosus. Cognitive dysfunction is the most common symptom of NPSLE. A variety of potential mechanisms or mediators related to the pathogenesis of NPSLE cognitive dysfunction have been proposed. However, the involvement of microglia CD40 has not been reported yet. This study aimed to investigate whether hippocampal microglia CD40 of MRL/MpJ-Faslpr (MRL/lpr) mice was involved in NPSLE cognitive dysfunction. This study found, using quantitative polymerase chain reaction, western blotting and immunohistochemistry, that hippocampal CD40 was aberrantly overexpressed in the MRL/lpr lupus mice. It also determined using flow cytometry and immunofluorescence that the aberrantly overexpressed CD40 was mainly derived from hippocampal microglia. The adeno-associated virus was used to inhibit microglia CD40 expression, and the brain damage and cognitive dysfunction of MRL/lpr mice improved. Also, imiquimod (IMQ)-induced lupus mice had the same NPSLE cognitive dysfunction, brain damage, and overexpressed hippocampal microglia CD40 as MRL/lpr mice. Therefore, IMQ-induced lupus mouse was proposed as one of the mouse models for studying NPSLE cognitive dysfunction for the first time in this study. The findings indicated that hippocampal microglia CD40 was involved in the development of NPSLE cognitive dysfunction, thus providing a novel research direction for the study of the pathogenesis of NPSLE.