Tumor Lymphatic Function Regulates Tumor Inflammatory and Immunosuppressive Microenvironments

Kataru, Raghu P.; Ly, Catherine; Shin, Jinyeon; Park, Hyeung Ju; Baik, Jung Eun; Rehal, Sonia; Ortega, Sagrario; Lyden, David; Mehrara, Babak J.

doi:10.1158/2326-6066.cir-18-0337

Cited by 40 publications

(30 citation statements)

References 55 publications

(60 reference statements)

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“…A recent experimental study showed that mice with ablated lymphatics exhibited reduced intra-tumoral accumulation of cytotoxic T cells and increased tumor PD-L1 expression, causing rapid tumor growth. Additionally, impaired function of the peritumoral lymphatic vessels resulted in decreased migration of dendritic cells to draining SNs compared with normal flank skin-draining lymph nodes [ 26 ].…”

Section: Discussionmentioning

confidence: 99%

Fewer tumour draining sentinel nodes in patients with progressing muscle invasive bladder cancer, after neoadjuvant chemotherapy and radical cystectomy

et al. 2019

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Purpose To examine the relationship between the number of tumour draining sentinel nodes (SNs) and pathoanatomical outcomes, in muscle-invasive bladder cancer (MIBC), in patients undergoing neoadjuvant chemotherapy (NAC) and radical cystectomy (RC). Materials and Methods In an ongoing prospective multicenter study, we included 230 patients with suspected urothelial MIBC from ten Swedish urological centers. All underwent TURb and clinical staging. From the cohort, 116 patients with urothelial MIBC; cT2-cT4aN0M0, underwent radical cystectomy (RC) and lymphadenectomy with SN-detection (SNd). 83 patients received cisplatin-based NAC and 33 were NAC-naïve. The number and locations of detected SNs and non-SNs were recorded for each patient. The NAC treated patients were categorized by pathoanatomical outcomes post-RC into three groups: complete responders (CR), stable disease (SD) and progressive disease (PD). Selected covariates with possible impact on SN-yield were tested in uni-and multivariate analyses for NAC-treated patients only. Results In NAC treated patients, the mean number of SNs was significantly higher in CR patients (3.3) and SD patients (3.6) compared with PD patients (1.4) (p = 0.034). In a linear multivariate regression model, the number of harvested nodes was the only independent variable that affected the number of SNs (p = 0.0004). Conclusions The number of tumor-draining SNs in NAC-treated patients was significantly lower in patients with progressive disease.

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Section: Discussionmentioning

confidence: 99%

Fewer tumour draining sentinel nodes in patients with progressing muscle invasive bladder cancer, after neoadjuvant chemotherapy and radical cystectomy

et al. 2019

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“…However, before cancer cells metastasize through these peritumoral lymphatics, tumor antigens (tAgs) and mature, activated dendritic cells presenting tAgs migrate through the peritumoral lymphatics to regional LNs to set up anti-tumor immune responses (Figure 1). Indeed, lymphangiogenesis and drainage to regional LNs may improve anti-tumor immune responses, as recently demonstrated by enhanced melanoma and breast cancer growth rates in preclinical models in which regional draining lymphatics were ablated [53].…”

Section: The Effects Of Metastasis and Cancer Progression On Lymphatimentioning

confidence: 92%

The Development and Treatment of Lymphatic Dysfunction in Cancer Patients and Survivors

Aldrich

Rasmussen

Fife

et al. 2020

Cancers

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Breast-cancer-acquired lymphedema is routinely diagnosed from the appearance of irreversible swelling that occurs as a result of lymphatic dysfunction. Yet in head and neck cancer survivors, lymphatic dysfunction may not always result in clinically overt swelling, but instead contribute to debilitating functional outcomes. In this review, we describe how cancer metastasis, lymph node dissection, and radiation therapy alter lymphatic function, as visualized by near-infrared fluorescence lymphatic imaging. Using custom gallium arsenide (GaAs)-intensified systems capable of detecting trace amounts of indocyanine green administered repeatedly as lymphatic contrast for longitudinal clinical imaging, we show that lymphatic dysfunction occurs with cancer progression and treatment and is an early, sub-clinical indicator of cancer-acquired lymphedema. We show that early treatment of lymphedema can restore lymphatic function in breast cancer and head and neck cancer patients and survivors. The compilation of these studies provides insights to the critical role that the lymphatics and the immune system play in the etiology of lymphedema and associated co-morbidities.

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“…Furthermore, in cancer, LVs transport tumor cells to the lymph nodes, triggering metastasis 22,23 . It is also known that tumor LVs induce tumor immune escape and evasion 24,25 . All of these examples show how the lymphatic vascular system is largely involved and implicated in major human diseases.…”

Section: Introductionmentioning

confidence: 99%

A bioengineered lymphatic vessel model for studying lymphatic endothelial cell‐cell junction and barrier function

2021

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Objective Lymphatic vessels (LVs) maintain fluid homeostasis by draining interstitial fluid. A failure in lymphatic drainage triggers lymphatic diseases such as lymphedema. Since lymphatic drainage is regulated by lymphatic barrier function, developing experimental models that assess lymphatic barrier function is critical for better understanding of lymphatic physiology and disease. Methods We built a lymphatic vessel‐on‐chip (LV‐on‐chip) by fabricating a microfluidic device that includes a hollow microchannel embedded in three‐dimensional (3D) hydrogel. Employing luminal flow in the microchannel, human lymphatic endothelial cells (LECs) seeded in the microchannel formed an engineered LV exhibiting 3D conduit structure. Results Lymphatic endothelial cells formed relatively permeable junctions in 3D collagen 1. However, adding fibronectin to the collagen 1 apparently tightened LEC junctions. We tested lymphatic barrier function by introducing dextran into LV lumens. While LECs in collagen 1 showed permeable barriers, LECs in fibronectin/collagen 1 showed reduced permeability, which was reversed by integrin α5 inhibition. Mechanistically, LECs expressed inactivated integrin α5 in collagen 1. However, integrin α5 is activated in fibronectin and enhances barrier function. Integrin α5 activation itself also tightened LEC junctions in the absence of fibronectin. Conclusions Lymphatic vessel‐on‐chip reveals integrin α5 as a regulator of lymphatic barrier function and provides a platform for studying lymphatic barrier function in various conditions.

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Tumor Lymphatic Function Regulates Tumor Inflammatory and Immunosuppressive Microenvironments

Cited by 40 publications

References 55 publications

Fewer tumour draining sentinel nodes in patients with progressing muscle invasive bladder cancer, after neoadjuvant chemotherapy and radical cystectomy

Fewer tumour draining sentinel nodes in patients with progressing muscle invasive bladder cancer, after neoadjuvant chemotherapy and radical cystectomy

The Development and Treatment of Lymphatic Dysfunction in Cancer Patients and Survivors

A bioengineered lymphatic vessel model for studying lymphatic endothelial cell‐cell junction and barrier function

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