Fetal exposure to oncoantigen elicited antigen-specific adaptive immunity against tumorigenesis

Abstract

BackgroundEnvisioned as a similar process to tumorigenesis in terms of biological behaviors and molecular basis, embryogenesis necessitates an immune surveillance system to eliminate erratically transformed cells. Our previous study demonstrated that fetal macrophage-like phagocytes triggered Th2-skewed immunity following endocytosing prenatally administered ovalbumin to facilitate postnatal allergic airway responses, highlighting the critical role fetal phagocytes played in dealing with antigens present in developing fetuses and shaping subsequent immune responses. It prompted us to examine whether fetuses could mount Th1 tumoricidal immunity against tumorigenesis following in utero exposure to tumor antigens.MethodsGestational day 14 murine fetuses underwent in utero injection of Th1-promoting human papilloma virus (HPV) E7 peptides. Postnatally, recipients were examined for immunological consequences and the resistance to TC-1 tumorigenesis.ResultsFetal exposure to HPV E7 did not cause tolerance but rather immunization in the recipients, characterized by proinflammatory Th1 polarization of their lymphocytes. Fetal macrophage-like phagocytes were responsible for taking up HPV E7 and triggering HPV E7-specific T-cell cytotoxicity and humoral immunity that rendered recipients resistant to TC-1 tumorigenesis in postnatal life. Adoptive transfer of HPV E7-loaded fetal phagocytes also elicited Th1 immunity with rapid expansion of HPV E7-specific cytotoxic CD8+ T-cell clones in response to TC-1 cell challenge so as to protect the recipients from TC-1 tumorigenesis, but failed to completely eliminate pre-existing TC-1 cells despite perceptible attenuation of local TC-1 tumor growth.ConclusionsOur study revealed that Th2-biasing fetus was not immune-privileged to foreign peptides, but competent to mount Th1 cytotoxic immunity and generate immunoglobulins against tumorigenesis following in utero exposure to Th1-promoting oncoantigen. It shed light on the role of fetal macrophage-like phagocytes in bridging toward tumor antigen-specific cellular and humoral immunity potentially as an immune surveillance system to eliminate transformed cells that might be egressing during embryogenesis and leftover until postnatal life.

Immunological Consequences of In Utero Exposure to Foreign Antigens

“…contact with alloantigens. Contrary to "actively acquired tolerance", in utero exposure to soluble ovalbumin (37), oncoprotein (38), or microbial antigens (39) triggered antigen-specific adaptive immunity. The immunogenicity in fetal life has a noteworthy relevance to human health such as prenatal initiation of allergy, immune surveillance against developmental tumorigenesis and prenatal immunization against infectious diseases.…”

“…Thus, fetal immunogenic capacity had the important implication for prenatal imprinting of atopy. Recently, we further disclosed that in utero exposure to oncoprotein triggered antigen-specific Th1 adaptive immunity to protect from tumorigenesis (38). It suggested the capacity of fetal immune system for immune surveillance against developmental tumorigenesis given an encounter with tumor antigens egressing during embryogenesis.…”

“…The pre-immune stage, usually referring to the period before full development of adaptive (T-cell) immunity, may not be early enough for the fetus to be "tricked" into ignoring nonself antigens as long as innate phagocytes remain functioning well and competent. Fetal macrophages were demonstrated to play a critical role in dealing with antigens present in utero and effectively retaining their memory after antigen internalization early before T-cell maturation so as to regulate the immunological outcome of fetal antigen exposure (37,38). The role of fetal macrophages in clonal deletion or tolerance induction to alloantigens awaits further experimental elucidations.…”

Fetal Macrophages Exposed to Salmonella Antigens Elicit Protective Immunity Against Overwhelming Salmonella Challenge in A Murine Model

“…This proof-of-principle experiment ( Figure 8 ) demonstrated that the developing fetuses, regardless of T-cell maturity, were competent to mount adaptive immunity in case of prenatal contact with microbial antigens and might be postnatally endowed with the capacity to defend against the pathogens from which the antigens derived. Taken together with the immunogenic outcome following in utero exposure to free peptide antigens of ovalbumin [ 16 ] and HPV E7 [ 17 ], it was hard to reconcile these results with Medawar’s actively acquired tolerance that in utero exposure to foreign antigens before full immune maturation led to tolerance. The innate fetal phagocytic system appeared to play a crucial role in triggering this acquired immune response because of its capacity for endocytosing foreign antigens at the pre-immune stage, usually referring to the period before full development of adaptive (T-cell) immunity.…”

“…Some animal studies even yielded conflicting results of alloreactivity to transplantation antigens in developing fetuses [ 13 , 14 , 15 ]. In our murine studies, effector functions by all arms of an adaptive immune system developed following in utero exposure to soluble peptide antigens regardless of lymphocyte maturity [ 16 , 17 ]. Such an event of in utero immunization could be attributed to fetal macrophage-like phagocytes (FMs), capable of taking up antigens for downstream immune signaling of antigen presentation [ 16 ].…”