Proton pump inhibitors have been explored for potentiating cancer therapies via reverting the tumor acidity and promoting the activation of anti-tumor immune responses. To regulate the intracellular pH of melanoma and immunosuppressive myeloid cells, we developed poly(L-lactide-co-glycolide) nanoparticles loaded with esomeprazole (ESO-NPs). The effect of ESO-NPs on melanoma cells was observed as alkalinization and reduction of melanin content accompanied by a decrease of microphthalmia-associated transcription factor (MITF), poliovirus receptor (PVR), and programmed death ligand 1 (PD-L1) immune checkpoint expression. ESO-NP treatment of melanoma-patient-derived and in vitro-induced myeloid-derived suppressor cells (MDSCs) reduced the expression of immunosuppression-associated molecules PD-L1, CD206, and CD163 on patient-derived myeloid cells while inducing the expression of co-stimulatory molecule CD86 and HLA-DR in the in vitro model. Our findings suggest that reprogramming the intracellular pH of melanoma and immune-suppression-associated myeloid cells with ESO-NPs can modulate the expression of proteins involved in resistance to cancer therapy and immunosuppression, thus potentially improving the response to immunotherapies.
© 2024 The Authors.

The human immunodeficiency virus epidemic continues in sub-Saharan Africa, and particularly affects adolescent girls and women who have limited access to antiretroviral therapy. Here we report that the risk of vaginal simian immunodeficiency virus (SIV)mac251 acquisition is reduced by more than 90% using a combination of a vaccine comprising V1-deleted (V2 enhanced) SIV envelope immunogens with topical treatment of the zinc-finger inhibitor SAMT-247. Following 14 weekly intravaginal exposures to the highly pathogenic SIVmac251, 80% of a cohort of 20 macaques vaccinated and treated with SAMT-247 remained uninfected. In an arm of 18 vaccinated-only animals without microbicide, 40% of macaques remained uninfected. The combined SAMT-247/vaccine regimen was significantly more effective than vaccination alone. By analysing immune correlates of protection, we show that, by increasing zinc availability, SAMT-247 increases natural killer cytotoxicity and monocyte efferocytosis, and decreases T-cell activation to augment vaccine-induced protection.
© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.

Neuroblastoma tumor-associated mesenchymal stromal cells (NB-TA-MSC) have been extensively characterized for their pro-tumorigenic properties, while their immunosuppressive potential, especially against NK cells, has not been thoroughly investigated. Herein, we study the immune-regulatory potential of six primary young and senescent NB-TA-MSC on NK cell function. Young cells display a phenotype (CD105+/CD90+/CD73+/CD29+/CD146+) typical of MSC cells and, in addition, express high levels of immunomodulatory molecules (MHC-I, PDL-1 and PDL-2 and transcriptional-co-activator WWTR1), able to hinder NK cell activity. Notably, four of them express the neuroblastoma marker GD2, the most common target for NB immunotherapy. From a functional point of view, young NB-TA-MSC, contrary to the senescent ones, are resistant to activated NK cell-mediated lysis, but this behavior is overcome using anti-CD105 antibody TRC105 that activates antibody-dependent cell-mediated cytotoxicity. In addition, proliferating NB-TA-MSC, but not the senescent ones, after six days of co-culture, inhibit proliferation, expression of activating receptors and cytolytic activity of freshly isolated NK. Inhibitors of the soluble immunosuppressive factors L-kynurenine and prostaglandin E2 efficiently counteract this latter effect. Our data highlight the presence of phenotypically heterogeneous NB-TA-MSC displaying potent immunoregulatory properties towards NK cells, whose inhibition could be mandatory to improve the antitumor efficacy of targeted immunotherapy.

Recently, a paradigm shift has been established for oncolytic viruses (OVs) as it was shown that the immune system plays an important role in the specific killing of tumor cells by OVs. OVs have the intrinsic capacity to provide the right signals to trigger anti-tumor immune responses, on the one hand by delivering virus-derived innate signals and on the other hand by inducing immunogenic cell death (ICD), which is accompanied by the release of various damage-associated molecules from infected tumor cells. Here, we determined the ICD-inducing capacity of Talimogene laherparepvec (T-VEC), a herpes simplex virus type 1 based OV, and benchmarked this to other previously described ICD (e.g., doxorubicin) and non-ICD inducing agents (cisplatin). Furthermore, we studied the capability of T-VEC to induce the maturation of human BDCA-1+ myeloid dendritic cells (myDCs). We found that T-VEC treatment exerts direct and indirect anti-tumor effects as it induces tumor cell death that coincides with the release of hallmark mediators of ICD, while simultaneously contributing to the maturation of BDCA-1+ myDCs. These results unequivocally cement OVs in the category of cancer immunotherapy.