Metastasis to vital organs is responsible for most cancer-associated deaths for solid tumors, yet for many cancers, lymph node metastases are observed prior to distant metastases.Clinically, nodal involvement is the most important prognostic indicator, yet the biological relevance of this involvement has remained unclear. Lymph nodes are the first sites of lymphatic drainage from tissues, including tumors, and lymph node metastases can seed distant metastases. Nonetheless, lymphatics and lymph nodes present distinct microenvironmental pressures from those of the blood and distant tissues. Lymph nodes also serve as central hubs of adaptive immune education, harbor the majority of tumor-reactive lymphocytes, and are critical orchestrators of immunotherapy responses. Thus lymph nodes are capable of both generating anti-tumor immunity and facilitating metastatic progression.Consequently, clinical management of lymph node metastases remains a fundamental challenge with conflicting evidence supporting conservative and aggressive approaches to surgery, radiation, and initiation of immunotherapy.This forum will bridge the basic cancer biology and immunology of lymph nodes with clinical insights and therapeutic strategies. Lymph node metastasis serves as a critical juncture in disease progression, and building across-disciplinary holistic understanding of the biology underpinning these processes will be necessary to improve clinical management of metastases and save the lives of the millions of cancer patients who succumb to metastatic disease each year.

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RELEVANCY

Recent clinical studies have placed lymph nodes in the spotlight of disease management. Deescalation trials in breast cancer and melanoma revealed no clinical benefit to lymphadenectomy in overall survival. Similarly lymph node sparing radiation approaches have been associated with improved responses to immune checkpoint blockade.Preclinical studies have implicated precursor T cell populations within lymph nodes as critical mediators of checkpoint response and neoadjuvant checkpoint trials in locally advanced resectable disease, wherein immunotherapy is administered prior to surgical resection of lymph nodes and primary tumors,have demonstrated improved outcomes over adjuvant therapy for multiple cancer types. Additionally, delivery of immunotherapies and novel adjuvants directly to lymph nodes reduces disease progression in animal models. Concurrently, new therapeutic advances targeting metabolic vulnerabilities and cell death pathways offer unique opportunities for therapeutically exploiting the distinct microenvironment of lymph. Thus, with the exponential growth in immunotherapy modalities, new small molecules and targeted approaches, combined with novel drug delivery strategies, strategies for treating patients with lymph node metastasis are perfectly poised for multi-disciplinary breakthroughs.

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GOALS

Bring together key experts from both clinical and fundamental science to share the most current data and develop an updated understanding of the role of lymph node metastasis in cancer progression and anti-cancer immunotherapy. Notably, only 4 of our proposed speakers have been to a prior Forbeck meeting, thus highlighting the further novelty of bringing lymphatic experts into the greater Forbeck community.

Identify critical decision points in clinical medicine in which choices are made out of necessity on incomplete evidence. Develop experimental strategies to address these critical gaps in knowledge.

Build and maintain new collaborations, particularly across clinical and fundamental science with the goal of utilizing the immunological power of lymph nodes while preventing disease progression from metastatic lymph nodes.

Key questions that will be discussed at this meeting include:

• How does the lymphatic microenvironment influence tumor progression and immune activation, and which of these mechanisms are targetable?
• What defines a therapeutically actionable lymph node metastasis - one to eradicate versus one to reprogram for immune benefit?
• How can preclinical models better recapitulate human lymphatic/tumor/immune interactions to guide drug development?
• Which molecular or cellular pathways within lymph nodes can be modulated to enhance immunotherapy efficacy while preventing metastatic spread?
• What clinical trial designs and collaborative frameworks are needed to translate lymphatic biology into new therapeutic strategies?