Human Papilloma Virus E7-loaded Fetal Macrophages Could Trigger E7-specific Th1 Immunity against TC-1 Tumorigenesis

Background: In our previous study, fetal exposure to ovalbumin caused Th2-skewed immunity. It was attributed to fetal macrophages that sequestered endocytosed ovalbumin, differentiated toward dendritic cells and later instruct T-cells as they fully developed to more efficiently deal with antigens.

Objective: This study was aimed to examine whether fetal macrophages could elicit Th1 immunity against tumor cells.

Methods: Fetal phagocytes from gestational day 14 C57BL/6 fetal liver and peritoneal cavity were in vitro pulsed with human papillomavirus (HPV) E7 peptides overnight.Then, they were transferred intraperitoneally into 4-6 week-old C57BL/6 mice. One month later, recipient mice were assessed for their T-cell activation by IL-2 release and T-cell polarization by IL-4, IL-5 and IFNγ secretion in the culture system under HPV E7 stimulation using ELISA. Lymphocyte proliferation was also measured by the incorporation of tritiated thymidine. Recipients were further evaluated for their resistance to TC-1 tumor cell challenge by monitoring tumor growth and recipient survival following subcutaneous inoculation of 10⁵TC-1 cells.

Results: After adoptive transfer of HPV E7-loaded fetal macrophages,recipient lymphocytes exhibited the activity of lymphocyte activation and proliferation specifically in response to HPV E7 stimulation as evidenced by significant IL2 secretion and tritium incorporation. Recipient lymphocytes displayed a Th1-skewed phenotype as evidenced by significant secretion of IFNγ rather than IL-4 and IL-5 under HPV E7 stimulation. Adoptive transfer of HPV E7-loaded fetal macrophages sufficed to protect the recipients from TC-1 tumorigenesis with tumor-free survivals of 70% at 2-month follow-up, but failed to completely eliminate pre-existing TC-1 cells despite perceptible attenuation of local TC-1 tumor growth.

Conclusion: Following endocytosis of tumor antigens, fetal macrophages could trigger tumor antigen-specific T-cell immunity to preclude tumorigenesis. It shed light on the crucial role of fetal macrophages in tumor immune surveillance, thereby eliminating transformed cells egressing during embryogenesis.