Implications of Lymphatic Transport to Lymph Nodes in Immunity and Immunotherapy

Thomas, Susan N.; Rohner, Nathan A.; Edwards, Erin E.

doi:10.1146/annurev-bioeng-101515-014413

Cited by 73 publications

(68 citation statements)

References 157 publications

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“…46,47 versus passive lymphatic drainage from the interstitial injection site. 16,19,48–50 Corroborating earlier reports, 36,51 we find retention within the injected skin to be size-dependent (Figure 2A), as is the relative selectivity of skin exposure to injected agent relative to systemic tissues (Figure 2B). When size matched, macromolecular and particulate retention in the skin is equivalent (Figure 2A), resulting in similar, although somewhat higher in the case of ~25–30 nm sized tracers, skin exposure (Figure 4C).…”

Section: Discussionsupporting

confidence: 88%

Flexible Macromolecule versus Rigid Particle Retention in the Injected Skin and Accumulation in Draining Lymph Nodes Are Differentially Influenced by Hydrodynamic Size

Rohner

Thomas

2016

ACS Biomater. Sci. Eng.

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Therapeutic immunomodulation in the skin, its draining lymph nodes, or both tissues simultaneously using an intradermal administration scheme is desirable for a variety of therapeutic scenarios. To inform how drug carriers comprising engineered biomaterials can be leveraged to improve treatment efficacy by enhancing the selective accumulation or retention of payload within these target tissues, we analyzed the influence of particle versus macromolecule hydrodynamic size on profiles of retention in the site of dermal injection as well as the corresponding extent of accumulation in draining lymph nodes and systemic off-target tissues. Using a panel of fluorescently labeled tracers comprising inert polymers that are resistant to hydrolysis and proteolytic degradation that span a size range of widely used drug carrier systems, we find that macromolecule but not rigid particle retention within the skin is size-dependent, whereas the relative dermal enrichment compared to systemic tissues increases with size for both tracer types. Additionally, macromolecules 10 nm in hydrodynamic size and greater accumulate in draining lymph nodes more extensively and selectively than particles, suggesting that intra- versus extracellular availability of delivered payload within draining lymph nodes may be influenced by both the size and form of engineered drug carriers. Our results inform how biomaterial-based drug carriers can be designed to enhance the selective exposure of formulated drug in target tissues to improve the therapeutic efficacy as well as minimize off-target effects of locoregional immunotherapy.

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Section: Discussionsupporting

confidence: 88%

Flexible Macromolecule versus Rigid Particle Retention in the Injected Skin and Accumulation in Draining Lymph Nodes Are Differentially Influenced by Hydrodynamic Size

Rohner

Thomas

2016

ACS Biomater. Sci. Eng.

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“…monocytes) have been associated both with inflammation (Gordon & Taylor, 2005; Robbins & Swirski, 2010) and several forms of psychosocial stress including low social economic status (Powell et al, 2013), perceived social isolation (Cole et al, 2015), and depressive symptoms in patients with coronary artery disease (Serfozo et al, 2016). In addition, secondary lymphoid tissue is an important initiator of the immune response, contains a high density of functional B cells (von Andrian & Mempel, 2003), and is an area of rapid turnover of B cells (Thomas et al, 2016). Given the functional importance of both monocytes and B cells within lymphoid tissue, the stress-induced alterations in gene regulation within these cell populations and inflammation- and interferon-related transcription factors give us an idea of the mechanism of how these cells populations are responding within the axillary LN.…”

Section: Discussionmentioning

confidence: 99%

Social regulation of the lymph node transcriptome in rhesus macaques (Macaca mulatta)

Chun¹,

Capitanio

Lamkin

et al. 2017

Psychoneuroendocrinology

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Previous research has shown that adverse social conditions may promote a conserved transcriptional response to adversity (CTRA) involving up-regulation of proinflammatory gene expression and down-regulation of Type 1 interferon anti-viral genes in circulating blood cells. However, the impact of social conditions on lymphoid tissue gene regulation remains largely unexplored. This project assessed how social instability in adult male rhesus macaques (N = 10, 5 in unstable, and 5 in stable social conditions) might regulate gene expression within secondary lymphoid tissue (lymph nodes; LN). Unstable social conditions down-regulated axillary LN expression of genes involved in Type I interferon anti-viral responses. Transcript origin analyses implicated monocytes and B cells as cellular mediators of these effects, and promoter-based bioinformatics analyses indicated reduced activity of AP-1, NF-κB, IRF, and CREB transcription factors within the axillary LN microenvironment. Although the current study is limited in sample size, these results suggest that social influences on immune cell gene regulation extend beyond the circulating leukocyte pool to alter generalized transcriptome profiles in secondary lymphoid tissue, and they do so in a regulatory program that resembles the pattern of antiviral inhibition previously observed in circulating leukocytes.

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“…Accordingly, CTLA-4’s suppression of anti-tumor immunity is considered to largely occur within secondary lymphoid organs (i.e. lymph nodes and spleen), tissues where T cell activation occurs [15–18] rather than within the tumor microenvironment. Since CTLA-4 is not expressed on the surface of naive and resting memory T cells [19], costimulation can occur upon antigen recognition.…”

Section: Checkpoints and Their Tissues Of Actionmentioning

confidence: 99%

“…To this end, microparticle-based formulations aiming to prolong the retention of therapeutic agent at the site of injection have emerged as an attractive strategy since increasing carrier size enhances and prolongs retention at the site of injection [55,56] (Figure 3). We also recently demonstrated for the first time that this principle is conserved in malignant tissues, resulting in sustained retention within the tumor after i.t injection, despite the remodeled, irregular, and leaky tumor vasculature (Figure 3) [18]. Material systems can additionally be engineered to control the release of agent from its carrier in order to prolong its therapeutic effects.…”

Section: Drug Delivery Systems Improving Checkpoint Blockade Mab Dmentioning

confidence: 99%

“…Second, one of the major tissues responsible for the priming of anti-tumor immune responses are tumor-draining lymph nodes [17]. This is because tumor antigens drain from the primary tumor microenvironment to the tumor-draining lymph node via the lymphatic vasculature [17,18,55]. Furthermore, tumor-draining lymph nodes often display altered immunological microenvironments relative to non-tumor associated lymph nodes, suggesting active regulation of the tumor-draining lymph node microenvironment by the tumor to suppress anti-tumor immunity.…”

Section: Opportunities and Potential Strategies For Improving Checmentioning

confidence: 99%

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Progress and opportunities for enhancing the delivery and efficacy of checkpoint inhibitors for cancer immunotherapy

Francis

Thomas

2017

Advanced Drug Delivery Reviews

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Despite the advent of immune checkpoint blockade for effective treatment of advanced malignancies, only a minority of patients respond to therapy and significant immune-related adverse events remain to be minimized. Innovations in engineered drug delivery systems and controlled release strategies can improve drug accumulation at and retention within target cells and tissues in order to enhance therapeutic efficacy while simultaneously reducing drug exposure in off target tissues to minimize the potential for treatment-associated toxicities. This review will outline basic principles of the immune physiology of checkpoint signaling, the existing knowledge of dose-efficacy relationships in checkpoint inhibition, the influence of administration route on treatment efficacy, as well as the resulting checkpoint inhibitor antibody biodistribution profiles amongst target versus systemic tissues. It will also highlight recent successes in the application of drug delivery principles and technologies towards augmenting checkpoint blockade therapy in cancer. Delivery strategies that have been developed for other therapeutic and immunotherapy applications with as-of-yet underexplored potential in checkpoint inhibition therapy will also be discussed.

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Implications of Lymphatic Transport to Lymph Nodes in Immunity and Immunotherapy

Cited by 73 publications

References 157 publications

Flexible Macromolecule versus Rigid Particle Retention in the Injected Skin and Accumulation in Draining Lymph Nodes Are Differentially Influenced by Hydrodynamic Size

Flexible Macromolecule versus Rigid Particle Retention in the Injected Skin and Accumulation in Draining Lymph Nodes Are Differentially Influenced by Hydrodynamic Size

Social regulation of the lymph node transcriptome in rhesus macaques (Macaca mulatta)

Progress and opportunities for enhancing the delivery and efficacy of checkpoint inhibitors for cancer immunotherapy

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