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  • br ACCEPTED MANUSCRIPT br Importantly TAF inactivation led t


    Importantly, TAF inactivation led to a partial reversal of stromal desmoplasia, partial normalization of tumor vasculature, decreased tumoral hypoxia, and improved tumor growth delay. They have used similar targeted NPs to modulate TAF-mediated cytokine signaling119. CXCL12 is an inhibitory chemokine that suppresses CD8+ T-cell recruitment. Systemic inhibitors of the CXCL12 axis are limited by systemic toxicity and poor tumor penetration. Anisamide-NP delivery of a CXCL12-trap plasmid successfully reduced CXCL12 secretion from TAFs and improved tumoral penetration of CD8+ T-cells in orthoptic KPC pancreatic tumors. The antitumor efficacy of this approach was markedly enhanced with the co-delivery of a PDL-1-trap plasmid to prevent TAF-mediated inactivation of infiltrating T-cells.
    Reversal of stromal desmoplasia and decreased inhibitory cytokine secretion can also be accomplished by targeted delivery of NPs encapsulating cytotoxic drugs to TAFs. The Huang group showed that anisamide-targeted dual delivery of gemcitabine and cisplatin can significantly reduce tumoral TAF populations, partially reverse stromal desmoplasia, and improve tumoral vascular permeability120. Other groups have found similar results with targeted NPs encapsulating docetaxel, doxorubicin, fraxinellone, and quercetin121-125. These studies support the hypothesis that it may be possible to selectively deplete TAFs to reverse tumoral desmoplasia and immunosuppressive cytokine signaling using systemically-administered, targeted NPs.
    3.4 Targeting Tumor Cells
    Tumor cells actively contribute to avoiding immune detection and can be targeted to enhance immune stimulation. Similar to inhibitory lymphocyte and macrophage populations, tumor cells excrete inhibitory cytokines to prevent APC and T-cell maturation/activation and maintain an immunosuppressive environment. The β-catenin pathway is an important mediator of this inhibitory signaling126. Matsuda et al. generated synthetic β-catenin-driven transgenic mouse models of HCC to demonstrate that NP-directed silencing of β-catenin signaling in tumor cells could decrease tumor growth and modulate the TME to improve responses to check point inhibitors127. In another study, lipid NP carriers of DRC-BCAT (an oligonucleotide targeting the CTNNB1 β-catenin gene) effectively modulated cytokine signaling to enhance CD8+ infiltration and growth arrest in multiple tumor models including B16F10, 4T1, and Neuro2A128. Further, the combination of the NP and dual CTLA-4/PDL-1 DL-Homocysteine blockade stimulated complete or near complete regression in a majority of tumors. These same anti-tumor effects were observed in spontaneous mammary tumors using a Wnt-driven MMTV-Wnt1 transgenic mouse model.
    Activation of proinflammatory signaling in tumor cells can also be achieved with nucleic DL-Homocysteine delivery. Agonists of the retinoic acid receptor gene 1 (RIG-1) can potently stimulate type-1 interferon responses and expression of other pro-inflammatory cytokines in tumor cells as well as other cell populations in the TME (including dendritic cells and TAMs)129. The Wilson group generated pH-responsive endosomolytic polymeric NPs to deliver intact 5’ triphosphate short double-stranded RNA (3pRNA) RIG-1 ligands130. The pH-responsive NPs enabled efficient endosomal escape and cytosolic delivery of the nucleic acid payload. Activation of RIG-1 triggered expression of proinflammatory cytokines, T-cell infiltration, and CD8+-mediated cytotoxicity in syngeneic CT26 models of colorectal cancer. When combined with anti-PD-1 blockade, complete regression of tumors was achieved in 30% of treated mice. It is worth noting that intratumoral delivery of 3pRNA robustly activated multiple cell populations in the TME and it is not currently clear to what extent the robust antitumor effect is mediated by effects in specific cell populations.
    Immune tolerance can also result as a byproduct of abnormal tumor physiology. Dysregulated tumor metabolism maintains a relatively hypoxic and acidic environment in the TME which is known to induce T-cell anergy. It may be possible to reverse this inhibitory environment by modulating tumor metabolism using NP nucleic acid delivery systems. A recent study engineered cationic lipid NP carriers for RNAi-mediated knock down of lactate dehydrogenase (LD) in tumor cells131. This significantly increased the pH of the tumor stroma and enhanced infiltration of CD8+ and NK-cells in addition to decreasing tumoral concentrations of M2 macrophages and Th2 T-regs. Silencing LD improved tumor growth delay on its own and markedly sensitized tumors to anti-PD-1 antibodies.
    4. Enhancing T-cell therapy
    T-cell therapies, in which patients are treated with tumor-targeted T-cells, have shown impressive efficacy in the treatment of hematogenous malignancies. T-cell therapy starts with the collection of immune cells from a cancer patient or healthy donor, followed by ex vivo genetic modification and expansion, and finally reinfusion to patient for cancer therapy132. FDA has approved two chimeric antigen receptor (CAR) T-cell therapies, Yescarta and Kymriah, for patients with lymphoma and leukemia, respectively132. However, several major challenges have obstructed the implementation of this paradigm as a standard-of-care in the treatment of solid tumors133. First, manufacturing of T-lymphocytes on a clinical scale is not easy because of the elaborate requirements for the isolation, genetic modification, and selective expansion of T cells, which entail specialized equipment and technical expertise that are not widely available134. Second, T-cell infiltration to solid tumors is hindered by downregulated chemokines, reduced expression of adhesion molecules on endothelial cells and disorganized tumor vasculature135. Lastly, transferred T-cells are facing a highly hostile TME filled with suppressive chemokines and cytokines secreted by T-regs or TAM, and PD-L1 expressed by tumor cells as well. In addition to the surrounding cells, the survival of T-cells is likely to be compromised by the low oxygen, low nutrient, and acidic conditions of the TME136.