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Brief description/objective

Lymph nodes (LNs) are situated at junctures of the blood vascular and the lymphatic system where antigens drain from peripheral tissues via afferent lymphatics. The decision whether and how immune responses against tumors are initiated and maintained is made in local tumor-draining LNs. During the development of malignant breast cancer, new LNs emerge within the glandular tissues that are normally devoid of LNs. However, we do not understand the mechanism of development of these LNs and their role in antitumor immunity. Thus, the novel hypothesis underlying the planned research is that de novo LNs appear in the vicinity of breast cancer as an accessory “base camp” for the initiation and maintenance of antitumor immunity. Here, we combine and leverage knowledge and experimental tools in immunology, vascular biology, cancer biology, and bioengineering to address the hypothesis in three specific aims:
1) To dissect the molecular pathways of tumor-induced development of accessory (a)LNs with a particular emphasis on lymphovasculokines.
2) To determined to which extent aLNs support antitumor immunity.
3) To stimulate formation of aLNs in mammary tissues to foster antitumor immunity.

The project is conceptually innovative because a deeper understanding of the interplay between aLNs and tumors may not only lead to a novel approach to cancer treatment, but could also help to establish a novel prevention paradigm in cancer medicine. The aims of the project will be addressed in a cooperative manner and activities in each group will contribute to address the global aims of the project. Gain of knowledge on the basic molecular principles involved in aLN formation (major aim 1) will absorb the major part of the activities. Determination of the impact of aLNs on antitumor immunity (major aim 2) will be assessed in cooperation between the three groups. Finally, formation of aLNs in tumor-draining areas in vivo (major aim 3) will be assessed by using highly innovative approaches including implantation of LN-like stromal cell spheroids and optogenetic induction of molecules that foster activation of the aLN anlage. In sum, the combination of the special expertise of the applicants in LN development, lymphovasculokine biology and optogenetic technology is crucial for addressing the ambitious project aims and therefore secures the basis for successful execution of the research plan.