Lymphangiogenesis-inducing vaccines elicit potent and long-lasting T cell immunity against melanomas

Abstract

In melanoma, the induction of lymphatic growth (lymphangiogenesis) has long been correlated with metastasis and poor prognosis, but we recently showed it can synergistically enhance cancer immunotherapy and boost T cell immunity. Here, we develop a translational approach for exploiting this “lymphangiogenic potentiation” of immunotherapy in a cancer vaccine using lethally irradiated tumor cells overexpressing vascular endothelial growth factor C (VEGF-C) and topical adjuvants. Our “VEGFC vax” induced extensive local lymphangiogenesis and promoted stronger T cell activation in both the intradermal vaccine site and draining lymph nodes, resulting in higher frequencies of antigen-specific T cells present systemically than control vaccines. In mouse melanoma models, VEGFC vax elicited potent tumor-specific T cell immunity and provided effective tumor control and long-term immunological memory. Together, these data introduce the potential of lymphangiogenesis induction as a novel immunotherapeutic strategy to consider in cancer vaccine design.

MHC Class II Antigen Presentation by Lymphatic Endothelial Cells in Tumors Promotes Intratumoral Regulatory T cell–Suppressive Functions

“…Although LECs are essential in the initiation of tumor-specific T-cell responses (50), tumoral LECs actively contribute to an immunosuppressive TME (30,32,50). Studies suggest, however, that immunotherapeutic approaches can overcome tumoral LEC immunosuppressive functions and that lymphangiogenesis may be beneficial for immunotherapies (33,51).…”

Development of Effective Tumor Vaccine Strategies Based on Immune Response Cascade Reactions

“…[ 132 ] Hu reported on the preparation of an oral DNA tumor vaccine that can overcome the human body's natural immune barrier by modifying the surface of bacteria; [ 133 ] however, in general, intramuscular injection, intradermal injection, and subcutaneous injection are still the mainstream of tumor vaccination, especially for the treatment of cancers with poor accessibility. [ 134 ] The development of new vaccine delivery methods may be a direction for future research. Moreover, the current assessment of immune response is the antigen‐specific antibody response, for example, neutralizing antibody titer or binding antibody titer determined by enzyme‐linked immunosorbent assay.…”

Infection-Induced Dermal Lymphatic Zippering Restricts Viral Dissemination from Skin and Promotes Anti-Viral CD8+ T Cell Expansion

“…4G) and suggests that management of the lymphatic vasculature may be a viable strategy for immunotherapy and vaccination. Though recent work has focused on expanding the lymphatic vasculature through overexpression of VEGFC to enhance LN transport and immune surveillance (Sasso et al, 2021), that lymphangiogenic-independent mechanisms could provide a novel strategy to modulate the inflammatory response will be interesting to explore moving forward.…”