Engineered Type 1 Conventional Dendritic Cell–Based Therapies for In Situ Cancer Immunization

Cancer immunotherapy, such as immune checkpoint inhibitors, Chimeric Antigen Receptor (CAR) T therapy, and cytokine therapy, have achieved successful improvement in extending survival in some patients. However, the immunosuppressive environment of solid tumors substantially compromises therapeutic outcomes and limits patient’s treatment options. Dendritic cells (DCs) are antigen-presenting cells (APCs) and play a critical role in immune modulation and communication with other immune cells, including CD8+ and CD4+ T cells. They internalize, process, present antigens to T cells, express costimulatory molecules, and secrete cytokines to modulate immune environment. Given this, engineering approaches to generate DC-based immunotherapies have been developed to treat multiple malignancies. Conventional dendritic cell vaccines rely on ex vivo antigen loading or in vivo targeting approaches utilizing antibody conjugation. However, antigens mismatch and suboptimal dendritic cell function may limit therapeutic efficacy. Type 1 conventional dendritic cells (cDC1s) are dendritic cell subsets specialized for cross-presentation and CD8+ T cell activation and have shown promise in initiating inflammatory antitumor immunity while maintaining and activating precursor exhausted T cells. In this thesis, we developed cDC1-based immunotherapies to reshape the tumor environments toward anticancer immunity. Antigen Capturing nanoparticle Transformed Dendritic Cell therapy (ACT-DC) was developed by integrating adoptively transferred cDC1s with antigen-capturing nanoparticles (AC-NPs), which were designed and synthesized to capture a wide range of tumor antigens while activating the co- injected cDC1s. This approach not only facilitated antigen presentation, as evidenced by significantly increased antigen-specific CD8 T cells, but also generated potent anticancer immune responses, achieving over 50% tumor-free survival and inducing long-term immune memory. Building upon the success of ACT-DC therapy, a cell-free platform for next generation cDC1-based immunotherapy was developed to enhance clinical translatability and reduce manufacturing complexity. Lipid nanoparticles loaded with a cDC1 differentiation-essential growth factor, FMS-like tyrosine kinase 3 ligand (Flt3L), were synthesized and intratumorally injected to induce Flt3L expression, resulting in cDC1 expansion and enabling in vivo cDC1 generation. With increased cDC1 population in tumors, Flt3L-LNPs enhanced T cell infiltration and modulated the immune environments in tumors and lymph nodes. Combination strategies using Flt3L-LNPs with immune checkpoint inhibitors and AC-NPs showed robust antitumor responses, achieving >50% tumor-free survival and indicating the promise of replacing adoptive cDC1 transfer. Collectively, this thesis demonstrates novel cDC1-based immunotherapeutic strategies that overcome key limitations of current dendritic cell-based therapies and efficiently inhibit tumor growth.

Author dc:creator

• Chih-Jia Chao (24400226)

• cDC1therapy

Statement dc:rights

• In Copyright
• Open Access after 2028-05-01

DOI dc:identifier

https://doi.org/10.25417/uic.32995271.v1

OAI identifier oai:identifier

oai:figshare.com:article/32995271