Abrogating Nanoparticle-induced Immunosuppression in Tumor Microenvironment

La-Beck, Ninh

Abstract

While nanoparticle (NP) drug delivery systems have been successful in improving drug tolerability, they have not produced major gains in patient overall survival. Moreover, although they interact with immune proteins and cells, the mechanisms and consequences of this on tumor progression are poorly understood. Since most marketed NPs are liposomes, we examined their effects on tumor growth and antitumor immunity in mice bearing syngeneic tumors. Importantly, we found that liposomes significantly enhanced tumor growth, and was associated with decreased production of interferon-gamma by tumor associated macrophages (TAMs) and cytotoxic T lymphocytes (CTLs), decreased numbers of tumor antigen specific CTLs, and decreased antigen presenting dendritic cells (APCs) in tumor draining lymph nodes of liposome treated mice, indicating inhibition of antitumor immune responses. Thus we hypothesize that liposomes induce immunosuppressive activity in TAMs, which in turn enhance tumor growth through inhibition of CTL and APC antitumor functions. We will test our hypothesis by pursuing the following specific aims: 1. Identify mechanisms by which liposomes modulate antitumor immunity and determine impact on tumor growth. We will treat immune competent mice bearing tumors with liposomes or control. The effects on TAM, CTL, and APC in tumors and tumor draining lymph nodes, as well as impact on tumor growth will be determined. To identify cell-cell interactions and cytokine pathways impacted by liposomes, ex vivo studies and in vitro co-culture studies will be used to evaluate responses to inflammatory stimuli and tumor antigens. The role of TAMs will be verified in similar experiments using mice with inducible macrophage deficiency. 2. Determine the effects of amino-bisphosphonates on tumor growth and immune responses induced by liposomes. To improve antitumor efficacy of liposomes, we propose to abrogate carrier-induced immunosuppression by loading alendronate into the carrier (pegylated liposomal alendronate; PLA) to ablate TAM function. We theorized that this approach will selectively deplete TAMs since this carrier preferentially accumulates in tumors, is phagocytosed by macrophages, and alendronate is cytotoxic to macrophages. We will treat immune competent mice bearing tumors with PLA or various controls, and examine the effects on antitumor immune responses and tumor growth. We expect that work proposed herein will identify and allow us to further target the immune pathways responsible for sub-optimal liposome efficacy. This will enable development of drug delivery systems exploiting desired or mitigating unwanted immune effects that can be broadly applied to treatment of diseases associated with immune dysfunction, including cancer. This proposal will also clarify the mechanisms through which TAMs regulate antitumor functions in CTLs and APCs. Thus this project has potential to significantly broaden current knowledge in the fields of drug delivery and tumor immunology.

Public Health Relevance

This proposal will identify novel mechanisms by which lipid nanoparticles (NPs) alter immune function and promote tumor growth, thereby enabling development of drug delivery systems exploiting desired or mitigating unwanted immune effects. The outcomes of studies using pegylated liposomal alendronate (PLA) to target and abrogate function of TAMs as a strategy to inhibit tumor growth have high potential to significantly improve the treatment of cancer. The individual components of PLA are already FDA-approved: alendronate is used for treatment of osteoporosis/metastatic bone resorption and the NP is used as a drug carrier for doxorubicin. Thus our results will have immediate clinical implications by swiftly translating into clinical trials. Since macrophage dysfunction is implicated in other healt conditions, the application of this strategy extends beyond cancer therapy.