Understanding the role of cDC1 heterogeneity for anti-cancer immunity

• Applicant: Dr. Jan Philipp Böttcher
• Subject Area: Immunology
• Term: since 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 449174900

Conventional type 1 dendritic cells (cDC1) are versatile orchestrators of immune responses against infection and cancer. In my postdoctoral work, I was able to show that tumor cDC1 are positively associated with human cancer patient survival in breast cancer, melanoma, lung cancer and head and neck squamous cell carcinoma (Böttcher et al., Cell, 2018). The importance of cDC1 in anti-tumor immunity is underscored by several studies with cDC1-deficient Batf3-knockout mice and other in vivo models of cDC1 depletion, which consistently display a loss of the ability to reject immunogenic tumors and are unable to support T cell–based immunotherapies. cDC1 are especially adept at taking up cellular material from (dying) cancer cells and recent studies demonstrated that CCR7+ cDC1 transport tumor antigens to tumor-draining lymph nodes, where they constitute the key population responsible for the cross-priming of naive tumor-specific CD8+ T cells. This functional role has long been considered the major reason why T cell-mediated cancer immunity is strictly dependent on tumor cDC1. However, recent work by me and others demonstrates that cDC1 fulfill an additional important role during the orchestration of cancer immunity that is carried out locally in tumor tissue. Here, cDC1 support cancer immunity by expanding tumor-specific T cells and boosting their anti-tumor activity by providing antigenic and stimulatory information. These findings demonstrate that successful anti-cancer immunity requires cDC1 to stimulate T cells at two distinct sites: locally within tumor tissue and after CCR7-dependent migration to tumor-draining lymph nodes. However, the underlying principles that regulate these two important processes and enable cDC1 to orchestrate cancer immunity locally in tumor tissue have hardly been investigated so far.In previous work, I have uncovered a so far unappreciated heterogeneity of activated cDC1 in tumor tissu,e evident as distinct cDC1 subpopulations. I hypothesize that this heterogeneity is highly relevant for cDC1-mediated cancer immunity. Thus, the main objective of this proposal is to investigate and understand how function and behavior of cDC1 and their heterogeneity in tumors is coordinated to ensure optimal support of T cell immunity. My previous findings suggest that local stimulation of T cells in tumors depends on a activated cDC1 subpopulation that remains in tumor tissue and is functionally distinct from those cDC1 leaving to tumor-draining lymph nodes. In this proposal, we aim to characterize the unique functional attributes of these cDC1 subpopulations in tumors and evaluate their role for anti-cancer immunity. Furthermore, we aim to identify the underlying mechanisms that govern the acquistion of cDC1 activation states in tumor tissue. Understanding the mechanisms that underly cDC1-mediated regulation of cancer immunity may help inform the development of novel strategies for cancer patient treatment.

• DFG Programme: Research Grants