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    r> Cell membrane-coated NPs have also been used to improve endogenous neoantigen recognition by APCs. In this technique, NP carriers are decorated with disrupted cell membranes and their associated cell surface proteins. Kroll et al. coated CpG-loaded PLGA NPs with B16F10 surface membranes75. They showed that the surface of the membrane-coated NPs contained multiple established tumor neoantigens including gp100, TRP-2, and melanin A. Significantly more (86%) mice were successfully vaccinated with these particles than with whole cells and CpG. Another group demonstrated similarly encouraging results with membrane-coated PLGA NPs encapsulating the TLR-7 agonist imiquimod76. These novel approaches demonstrate that it may be possible to stimulate polyclonal systemic immune responses without any upfront identification of specific tumor neoantigens in individual patients using novel nanomedicines.
    3.2 Nicotine Activating Effector Cells
    Activated CD8+ T-cells are the key effectors of tumor-specific (adaptive) immunity. Even if clonal antitumor T-cells that can recognize and attack tumor cells are generated, they must efficiently infiltrate the tumor stroma and remain activated in order to be effective. T-cell-mediated cytotoxicity is a tightly regulated process. Numerous receptors are expressed on the T-cell surface that can stimulate or inhibit the activity of activated T-cells77. Inhibitory receptors include CTLA-4 (CD152), PD-1 (CD279), TIM-2, and LAG-3 (CD223). Many tumors express ligands to these receptors, such as PDL-1, in an effort to reduce the activation and maturation of APCs and infiltrating CD8+ T-cells. Inhibitory Nicotine to CTLA-4 and PD-L1 are far and away the most successful cancer immunotherapies to date. However, they are not
    without limitations. Among immunogenic histologies like NSCLC, they are only effective in tumors that overexpress the PD-L1 ligand78. Durable response rates in PD-L1 overexpressing tumors are generally less than 50%. Many non-immunogenic tumors, including MSS colorectal tumors, express high levels of PDL-1 but are not responsive to anti-PD-1 therapies79,80. Natural killer (NK) cells are also important innate (antigen non-specific) cytotoxic effector cells. They harbor inhibitory surface receptors such as CD47 that can be overexpressed by tumors to avoid clearance by the innate immune system81. Intensive research has been dedicated to identifying novel methods of improving the activation of effector cells in the TME.
    3.2.1 Enhancing T-cell Checkpoint Inhibition
    NP delivery has been used to improve the efficacy of CTLA-4 and PDL-1 inhibitors by providing sustained release in tumors and co-delivery with other immune adjuvants. One group engineered photodegradable PLA NPs co-encapsulated with hollow gold nanoshells and anti-PD-1 peptide (APP)82. These particles enabled sustained release of APP for up to 40 days. Accelerated release could be stimulated with a near infrared laser. In a metastatic model system, laser-irradiation of “primary” tumors stimulated partial regression and growth delay in the laser-treated and distant tumor deposits indicating the activation of a systemic immune response. Zhen Gu and his group developed a cleavable nucleic acid-based NP comprised of the potent immune-stimulant CpG-ODN to deliver anti-PDL-1 antibodies83. The nucleic acid shell was constructed with ssDNA and CpG repeats with cutting sites for the restriction enzyme HhaI. HhaI was caged in triglycerol monostearate NPs attached to the larger DNA NPs which could be enzymatically-cleaved by wound-responsive esterases and matrix metalloproteinases. Wound-associated inflammation (triggered by partial tumor resection) resulted in degradation of the DNA carrier and release of anti-PDL1 antibodies and CpG-ODN fragments. Systemic NP administration and subtotal tumor resection stimulated complete tumor rejection in 40% of mice, whereas no complete rejections were observed with systemic co-administration of CpG-ODN and anti-PDL-1 antibodies.