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Interactions between different cell types in the tumor microenvironment (TME) affect tumor growth. Tumor-associated fibroblasts produce C-X-C motif chemokine ligand 13 (CXCL13) which recruits B cells to the TME. B-cells in the TME differentiate into regulatory B cells (Bregs) (IL-10 + CD1d + CD5 + CD138 + CD19 + ). We highlight these Breg cells as a new important factor in the modulation of the immunosuppressive TME in different desmoplastic murine tumor models. In addition, CXCL13 also stimulates epithelial-mesenchymal transition (EMT) of the tumor cells. The tumorigenic roles of CXCL13 led us to explore an innovative anti-cancer strategy based on delivering plasmid DNA encoding a CXCL13 trap to reduce Bregs differentiation and normalize EMT, thereby suppressing tumor growth. CXCL13 trap suppressed tumor growth in pancreatic cancer, BRAF-mutant melanoma, and triple-negative breast cancer. In this study, following treatment, the affected tumor remained dormant resulting in prolonged progression-free survival of the host., (Copyright © 2022. Published by Elsevier B.V.)

Immune responses against polyethylene glycol (PEG) can lead to the rapid clearance of PEGylated drugs and are associated with increased risk of serious adverse events such as infusion reactions and anaphylaxis. Although select PEGylated therapeutics can induce anti-PEG antibodies (APA), there is currently no readily deployable strategy to mitigate their negative effects. Given the large number of PEGylated therapeutics that are either FDA-approved or in clinical development, methods that suppress APA induction to ensure the safety and efficacy of PEGylated drugs in patients would be a valuable clinical tool. We previously showed that infusion of high molecular weight (MW) free PEG can safely and effectively restore the circulation of PEG liposomes in animals with high pre-existing titers of APA, without stimulating additional APA production. Here, we explored the effectiveness of prophylaxis with free PEG or tolerogenic PEGylated liposomes as a strategy to reduce the amount of APA induced by subsequently administered PEGylated liposomes. Surprisingly, we found that a single administration of free PEG alone was capable of markedly reducing the APA response to PEG-liposomes for ~2 months; the effectiveness was comparable to, and frequently exceeded, interventions with different tolerogenic PEG-liposomes. These results support further investigations of free PEG prophylaxis as a potential strategy to ameliorate the APA response to sensitizing PEGylated therapeutics., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Triple negative breast cancer (TNBC) does not respond to checkpoint blockade immunotherapy as a result of immunosuppressive tumor microenvironment. To remodel the tumor microenvironment, we developed a liposome formulation to deliver a potential immunogenic cell death (ICD) inducing agent, 17-(allylamino)-17-demethoxygeldanamycin (17-AAG, or tanespimycin), in a tumor targeted manner to reverse the immunosuppressive microenvironment and facilitate the checkpoint blockade immunotherapy. The 17-AAG liposomes was prepared by thin film dispersion methods. The orthotopic 4T1 murine triple negative breast cancer model was studied. 17-AAG delivered by liposome remodeled the immunosuppressive microenvironment, significantly increased tumor infiltrating T cells, lowered the hypoxia level, decreased the suppressive lymphocytes such as tumor associated macrophages and myeloid derived suppressor cells in the tumor microenvironment. In addition, real-time PCR analysis revealed that chemokines and cytokines with immunosuppressive properties were notably reduced, which further facilitated the T cell mediated immunotherapy. Despite the fact that low dose 17-AAG liposomes demonstrated a limited therapeutic effect alone on 4T1 tumor, promising efficacy was observed when 17-AAG liposomes combined with checkpoint blockade immunotherapy. Taken together, 17-AAG liposomes could remodel the immunosuppressive microenvironment of triple negative breast cancer and facilitate the checkpoint blockade immunotherapy., Competing Interests: Declaration of Competing Interest LH is a member of the scientific advisory board for PDS Biotechnology, Inc., Beijing Inno Medicine and Samyang Biopharmaceutical Co. Other authors declare no competing interest., (Published by Elsevier B.V.)

Phosphoinositide-3-kinases (PI3Ks) are part of signal transducing enzymes that mediate key cellular functions in cancer and immunity. PI3K-γ is crucial for cellular activation and migration in response to certain chemokines. PI3K-γ is highly expressed in myeloid cells and promotes their migration and the production of inflammatory mediators. We found that PI3K-γ was also highly expressed in tumor-associated B cells. IPI-549, the only PI3K-γ inhibitor in clinical development, offers a unique approach to enhance the anti-tumor immune response. We encapsulated IPI-549 in targeted polymeric nanoparticles (NP) and tested its activity in both murine pancreatic cancer and melanoma models. IPI-549 NP significantly decreased tumor growth and prolonged host survival in both models. Importantly, IPI-549 NP treatment reduced the suppressive tumor microenvironment by decreasing both suppressive myeloid and plasma cells in the tumor. We concluded that IPI-549 NP delivery could be a promising method for treating pancreatic cancer and other immune-suppressive tumors., (Copyright © 2019 Elsevier B.V. All rights reserved.)