New insights into the pathophysiology of lymphedema are providing targets for future treatment interventions to cure and prevent the disease, according to our recent research.
Previously, it was believed that the lymphatic vasculature played a passive role by transporting antigen-presenting cells and soluble antigens to regional lymph nodes. However, the most recent studies show that lymphatic endothelial cells regulate immune responses more directly. They control the entry of immune cells into lymphatic capillaries, present antigens on major histocompatibility complex proteins, and modulate antigen-presenting cells. (1)
We recently published a review in Frontiers in Immunology summarizing the current understanding of the cellular mechanisms driving the development of lymphedema. The review is based on our published work in mouse models in the Babak Mehrara lab at Memorial Sloan Kettering Cancer Center, which focuses on lymphedema and lymphatic biology, and also incorporates findings from other researchers around the world. (1)
In this clinical update, we provide an overview of lymphedema and its burden on patients, and insights from three of our most recently published papers on the cellular processes driving the disease. We also discuss our efforts at MSK to prevent and treat lymphedema in people with cancer using microsurgery techniques.
At MSK, our research team is dedicated to investigating the factors that contribute to the development of lymphedema so that one day we may find a cure. There are no other cancer centers with an active lymphedema surgical program supported by a dedicated lymphedema research laboratory.
Lymphedema is a chronic disease that involves the accumulation of interstitial fluid and fat in tissues. In developed countries, it occurs most commonly after lymph node dissection for cancer treatment. (2) Most patients who undergo lymph node dissection for solid malignancies — such as breast cancer, melanoma, gynecologic or urologic tumors, or sarcomas — experience minor swelling that resolves on its own two to six weeks after surgery. But about 20 to 40 percent of these patients go on to develop lymphedema eight to 24 months postsurgery. (3)
Lymphedema is a disabling condition that involves fibro-adipose deposition in the affected limb. An estimated five to ten million Americans suffer from the disease, and the majority of those affected are breast cancer survivors, many of whom have undergone breast reconstruction. (1) Patients with lymphedema have a lower quality of life due to stiffness, pain, and in some cases, recurrent infections. (4) Many cancer survivors consider managing lymphedema more difficult than their original cancer treatment because it is a chronic and progressive disease with no cure. Palliative treatment approaches that rely on manual massage and tight-fitting garments to prevent fluid accumulation are a constant reminder of cancer diagnosis and treatment. (2)
New Insights about the Pathophysiology of Lymphedema
Recent findings suggest that abnormalities in lymphangiogenesis alone are not enough to cause lymphedema. Rather, lymphatic injury appears to be an initiating factor that sets other pathological changes into motion, resulting in lymphedema many months after surgery. (1)
Traditionally, it was believed that the lymphatic vasculature played a passive role in lymphedema, controlling immune responses indirectly by modulating the rate of delivery of antigens and cells to regional lymph nodes by controlling lymphatic vessel tone and pumping. (5), (6), (7), (8) However, more recent research has shown that the lymphatic system also plays an active role. Researchers have discovered that lymphatic endothelial cells actively regulate the entry of immune cells into lymphatic capillaries, present antigens on major histocompatibility complex proteins, and modulate antigen-presenting cells. (1)
Recent studies from our lab and others have shown that lymphatic injury results in chronic inflammatory changes in the skin distal to the site of injury. These changes regulate the development of lymphedema by permitting lymphatic leakiness, decreasing lymphatic pumping, increasing tissue fibrosis, and impairing the development of collateral lymphatics. (1)
Mehrara Lab Insights
Highlights of the findings from three of our most recently published papers on the cellular mechanisms of lymphedema and the potential clinical implications are as follows: (1)
Regulatory T cells mediate local immunosuppression in lymphedema.
Axillary lymph node dissection, both in the clinic and in mouse models, results in a marked increase in the number of regulatory T cells (Tregs) in the affected limb. We studied the role of Tregs in mouse models of immunosuppression. We found that Treg proliferation in tissues distal to the site of lymphatic injury contributed to impaired innate and adaptive immune responses, making it difficult to clear infections and mount effective immune responses. (9)
Importantly, we also demonstrated that the depletion of Tregs in the setting of lymphatic injury restored critical immune-mediated responses. Our findings provide additional evidence that immune responses following lymphatic injury play a critical role in mediating the pathology of lymphedema. (9)
Lymphedema begins after activated CD4+ T cells in regional lymph nodes migrate to skin.
Using a technique where we injected tagged T cells in mice that lack CD4 cells (CD4 knockout), we demonstrated that T cell activation following lymphatic injury occurs in regional skin-draining lymph nodes after interaction with antigen-presenting cells, such as dendritic cells. The activated CD4+ T cells differentiated into a mixed T helper type 1 and type 2 phenotype, and also upregulated the expression of adhesion molecules and chemokines that guide their migration to the lymphedematous limb skin. (10)
Importantly, we found that the release of activated T cells from lymph nodes into the systemic circulation via sphingosine 1 phosphate (SIP) signaling was necessary for lymphedema to develop. Blocking this T cell release using a SIP inhibitor prevented lymphedema from developing, suggesting that this approach may have clinical utility as a treatment strategy in the future. (10)
T helper 2 differentiation is necessary for the development of lymphedema.
T cells infiltrating lymphedematous tissues have a mixed T helper (Th) 1 and Th2 differentiation profile. In preclinical models, treatment with neutralizing antibodies targeting cytokines that promote Th2 differentiation into interleukin 4 (IL-4) and interleukin 3 (IL-3) decreased the severity of lymphedema, suggesting that Th2 cells play a key role in disease processes. However, these studies did not explore the contribution of Th1 cells nor determine whether IL-4 and IL-3 blockade act mainly on T cells or reduce lymphedema in other ways. (11)
In our study, we analyzed the effect of lymphatic injury in transgenic mice with defective Th1 and Th2 cells. We found that Th2-deficient mice were protected from developing lymphedema, had decreased levels of fibrosis, increased collateral vessel formation, and preserved lymphatic vessel pumping function. In contrast, Th1-deficient mice developed lymphedema with the same severity as wild-type controls. (11)
Therefore, we concluded that Th2 differentiation is necessary for the development of lymphedema following lymphatic injury. These findings are important, since immunotherapy directed at Th2 cells is well studied and found effective in treating such diseases as asthma and atopic dermatitis. In the future, immunotherapy targeted at Th2 cells may be a potentially useful treatment approach to reduce lymphedema. (11)
Preventing and Treating Lymphedema
The sentinel lymph node approach to assess nodes and only remove those with metastases has helped minimize the risk of lymphedema in a variety of malignancies, such as breast cancer, endometrial cancer, and melanoma.
We are also pioneering microsurgical techniques that redirect or reconnect small lymphatic and blood vessels to help prevent or treat lymphedema. The microsurgical techniques involve transplanting lymph nodes from one part of the body to another and reconnecting small blood vessels using advanced surgical microscopy. In other procedures, we can redirect lymphatic vessels to regional blood vessels (lymphovenous bypass). These procedures can also be performed in some patients at the time of axillary lymph node dissection to prevent the development of lymphedema. Dr. Mehrara and his colleagues Dr. Dayan and Dr. Coriddi have lectured nationally and internationally on breast reconstruction and have published extensively on the topic.
The review was supported by a National Institutes of Health R01 grant (HL111130-01) and an institutional grant (P30 CA008748). The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.