Promoting Anti-cancer Immune Responses Using Lethally Irradiated Tumor Cells


Summary

Sasso et al. developed a cancer vaccine based on lymphangiogenesis-associated T cell immunity using lethally irradiated tumor cells. They tested the vaccine in mice and found that the vaccine induced tumor growth inhibition in all recipient animals. Moreover, when tumor cells were reintroduced after 10 months, immune memory remained and prevented the growth of new tumors. Those results indicated that the vaccine could elict long-lasting anti-cancer protection as well as treat already existing tumors.

Background

Tumor lymphangiogenesis is associated with multiple immune regulatory processes leading to an immune-infiltrated tumor microenvironment and can be theoretically exploited to boost anti-tumor immunity. Nevertheless, previous reports have already shown that the direct stimulation of tumor-associated lymphangiogenesis could also promote cancer cell dissemination and metastasis, posing a new threat to patients' health after the treatment (Farnsworth et al. 2018). Therefore, Sasso et al. sought to develop a therapeutic lymphangiogenic vaccine that harnesses lymphatics-induced immune responses andavoids direct involvement of lymphatic vessels within the tumor (Sasso et al. 2021).

Experiment

To begin with, mouse melanoma cells were selected as the treatment target and genetically modified to overexpress vascular endothelial growth factor C (VEGF-C), a protein that promotes lymphangiogenesis.

Then, the researchers asked whether melanoma cells overexpressing VEGF-C and after being lethally irradiated could induce local lymphangiogenesis and boost anti-tumor immune responses in the mouse cell injection site. With a positive experimental result, they went further to develop a VEGFC vaccine based on those melanoma cells.

Realizing the synergistic effect between lymphangiogenesis and immune activation can be increased by using locally retained immune adjuvants. The researchers administered intradermallya variant of an anti-CD40 antibody containing a conjugated peptide domain derived from placenta growth factor-2 (PIGF-2123-144).  This peptide domain extends the residence time of the antibody at the injection site, therefore increasing local antigen presenting cell (APC) maturation and activation. PIGF-2123-144 used in this study was synthesized with >95% purity by GenScript (Ishihara et al. 2018).

The newly developed vaccine was injected into mice and evaluated in a melanoma model for its prophylactic and therapeutic efficacy.

Results

Seventeen days after injection of lethally irradiated melanoma cells and topical adjuvants, experimental mice developed more enhanced antigen-specific T cell responses than those in the control group. Vaccinations with a VEGFC vaccine caused complete prevention of tumor growth in all the recipient mice, whereas non-lymphangiogenic vaccine with equivalent composition only offered partial protection against melanoma.

In a follow-up assessment, strong memory responses were still observed to protect the mice against a second tumor injection 320 days after the initial immunization, with half of the mice overcoming the challenge.

In addition to protective immunity induction, the VEGFC vaccine could also serve as a therapeutic method for treating existing tumors. In a melanoma mouse model, significantly delayed tumor growth was observed after injection of the vaccine, and no formation of metastases was found in all recipient mice.

In summary, these results reveal the capacity of lymphangiogenic vaccines to promote a potent anti-cancer T cell immunity and suggest a new protective and therapeutic approach to fight solid tumors.

Reference

Farnsworth, Rae H., Marc G. Achen, and Steven A. Stacker."The evolving role of lymphatics in cancer metastasis." Current opinion in immunology 53 (2018): 64-73.

Sasso, Maria Stella, et al. "Lymphangiogenesis-inducing vaccines elicit potent and long-lasting T cell immunity against melanomas." Science Advances 7.13 (2021): eabe4362.


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