Exploring dendritic cell heterogeneity in tumors: From preclinical models to therapeutic applications

Dendritic cells (DCs) are cells of the immune system that serve as the “security guards” of the body by constantly patrolling the body for issues such as infections or tumors and are critical in orchestrating anti-tumor immunity. Evidently, their investigation as an anti-cancer therapy is warranted. However, multiple studies have described several DC types, often using inconsistent nomenclature, complicating translation across studies. To bridge this knowledge gap, we generated pan-cancer mouse and human tumor-associated DC (TADC) atlases using single-cell RNA sequencing, encompassing 14 mouse tumor models and 10 human cancer types, thoroughly characterizing the TADC compartment. TADCs were found to be broadly conserved between mice and humans, although species-specific differences were evident. Moreover, a comprehensive assessment of how different human TADCs associate with patient survival outcomes was performed.

With a thorough understanding of the TADC compartment, we aimed to assess the potential of DCs as an anti-cancer therapy. For this, we focused on ovarian cancer, wherein even with current advancements in therapies, 40% of patients still die from the disease. However, currently used ovarian cancer mouse models are not optimally translatable to patients, given that most often ovarian cancer cell lines are inoculated intraperitoneally to establish a “metastatic model”. Alternatively, currently available orthotopic ovarian cancer models are rather slow progressing and fail to reach Stage IV of the cancer, which is seen in ovarian cancer patients at diagnosis. To address these constraints, we developed a fast-progressing orthotopic ovarian cancer mouse model that replicates Stages I-IV seen in ovarian cancer patients. Furthermore, in-depth characterization of the immune compartment in ovarian cancer tumors and other relevant organs, along with a thorough profiling of the metastatic dissemination process, allowed a better understanding of this model and its congruence with ovarian cancer patients.

To evaluate the potential of DCs as anti-cancer therapy against ovarian cancer, we performed prophylactic and therapeutic vaccinations using TADCs. Moreover, as an alternate therapeutic strategy against ovarian cancer, we used AXL-targeting nanobodies, given that AXL is highly expressed in ovarian cancer patients and correlates with a worse prognosis. We found that anti-AXL nanobodies trigger cell death of ovarian cancer cells and act synergistically with Olaparib to suppress ovarian cancer cell proliferation.

Overall, the different chapters of this thesis follow a logical progression from investigating dendritic cell heterogeneity, to developing a highly patient translatable mouse model and the testing of novel therapies against this model, providing useful resources to the field for further investigation and validation.