miR-146a inhibits ovarian tumor growth in vivo via targeting immunosuppressive neutrophils and enhancing CD8+ T cell infiltration.

Immunotherapies have emerged as promising strategies for cancer treatment. However, existing immunotherapies have poor activity in high-grade serous ovarian cancer (HGSC) due to the immunosuppressive tumor microenvironment and the associated low tumoral CD8+ T cell (CTL) infiltration. Through multiple lines of evidence, including integrative analyses of human HGSC tumors, we have identified miR-146a as a master regulator of CTL infiltration in HGSC. Tumoral miR-146a expression is positively correlated with anti-cancer immune signatures in human HGSC tumors, and delivery of miR-146a to tumors resulted in significant reduction in tumor growth in both ID8-p53-/- and IG10 murine HGSC models. Increasing miR-146a expression in tumors improved anti-tumor immune responses by decreasing immune suppressive neutrophils and increasing CTL infiltration. Mechanistically, miR-146a targets IL-1 receptor-associated kinase 1 and tumor necrosis factor receptor-associated factor 6 adaptor molecules of the transcription factor nuclear factor κB signaling pathway in ID8-p53-/- cells and decreases production of the downstream neutrophil chemoattractant, C-X-C motif chemokine ligand 1. In addition to HGSC, tumoral miR-146a expression also correlates strongly with CTL infiltration in other cancer types including thyroid, prostate, breast, and adrenocortical cancers. Altogether, our findings highlight the ability of miR-146a to overcome immune suppression and improve CTL infiltration in tumors.

Nano-therapeutics for modulating the tumour microenvironment: Design, development, and clinical translation.

Nanoparticles (NPs) that permit active targeting promise to play a key role in cancer therapy moving forward. However, in order to successfully advance into clinic, these delivery platforms not only must target individual tumoural cellular components but also require safe, efficient and scalable production. Herein, we review recent and innovative targeted nanoparticle delivery strategies to individual TME components, including cancer-associated blood and lymphatic vessels, pericytes, cancer associated fibroblasts, and cancer stem cells. In contrast to traditional therapies that promote widespread ablation, emerging nano-strategies that specifically modulate different cell populations of the TME, such as targeting pericytes and endothelial cells for vascular normalization, are proving to effectively deliver therapeutics to tumours. Additionally, new smart targeted NPs with transformable characteristics responsive to specific tumour microenvironmental cues demonstrate enhanced spatiotemporal control over cell targeting and therapeutic release. However, translating these therapies to the clinic requires overcoming several significant barriers such as failure to recapitulate the human TME in animal models and issues with NP targeting efficacy, safety and scalable production. We discuss recent efforts to overcome these challenges and innovative means to reduce off-target toxicities. We also highlight important deficiencies in current NP development and offer new perspectives on the design of pre-clinical and clinical trials to accelerate clinical translation of targeted NP platforms.