Parenteral is more efficient than mucosal immunization to induce regression of human papillomavirus‐associated genital tumors

Abstract

Cervical cancer is a public health concern as it represents the second cause of cancer death in women worldwide. High-risk human papillomaviruses (HPV) are the etiologic agents, and HPV E6 and/or E7 oncogene-specific therapeutic vaccines are under development to treat HPV-related lesions in women. Whether the use of mucosal routes of immunization may be preferable for inducing cell-mediated immune responses able to eradicate genital tumors is still debated because of the uniqueness of the female genital mucosa (GM) and the limited experimentation. Here, we compared the protective activity resulting from immunization of mice via intranasal (i.n.), intravaginal (IVAG) or subcutaneous (s.c.) routes with an adjuvanted HPV type 16 E7 polypeptide vaccine. Our data show that s.c. and i.n. immunizations elicited similar frequencies and avidity of TetE7 1 CD81 and E7-specific Interferon-gamma-secreting cells in the GM, whereas slightly lower immune responses were induced by IVAG immunization. In a novel orthotopic murine model, both s.c. and i.n. immunizations allowed for complete long-term protection against genital E7-expressing tumor challenge. However, only s.c. immunization induced complete regression of already established genital tumors. This suggests that the higher E7-specific systemic response observed after s.c. immunization may contribute to the regression of growing genital tumors, whereas local immune responses may be sufficient to impede genital challenges. Thus, our data show that for an efficiently adjuvanted protein-based vaccine, parenteral vaccination route is superior to mucosal vaccination route for inducing regression of established genital tumors in a murine model of HPV-associated genital cancer.Vaccination strategies that elicit cell-mediated immunity in the genital mucosa (GM) may be critical for protection against pathogens that use this mucosa as entry and replication site. This may be especially relevant in the case of genital human papillomavirus (HPV), as persistent infection with the high-risk types, most often HPV type 16 (HPV16), may lead to malignant diseases, including cervical cancer, 1 the second leading cause of cancer death in women worldwide.2 The available prophylactic vaccines prevent HPV infections through the induction of neutralizing antibodies, but they possess no therapeutic effects on already established HPV infections or associated lesions.3 Control of these lesions by cell-mediated immune responses is demonstrated by their increased prevalence when cell-mediated immunity is impaired [4][5][6] and by the finding that early infiltration of highly cytotoxic effector T cells in low-grade genital lesions appears to provide protection against tumor progression. 7 Thus, induction of cell-mediated immune responses against the HPV oncogenes (E6 and/or E7), which are implicated in initiation and maintenance of high-grade anogenital lesions, became an attractive approach, though with limited clinical success to date. 8 The most promising results [i.e., 47% regression of vulvar int...

Intravaginal immunization with HPV vectors induces tissue-resident CD8+ T cell responses

“…There are numerous reports of the induction of CD8 + T cell responses in the cervicovaginal mucosa after systemic vaccination with non-replicating vectors (7,11,13,46), and we confirmed these observations using our Ad5-MM2 vector in an intramuscular prime/boost regimen. However, this regimen was qualitatively and quantitatively inferior to the Ivag prime/boost immunization regimen.…”

“…Furthermore, several systemic immunization strategies using live viruses, replication-defective viral vectors, or protein antigens and adjuvant have been shown to induce CD8 + T cell responses in the cervicovaginal mucosa in addition to systemic CD8 + T cell responses (11)(12)(13). Nevertheless, T cell trafficking is clearly regulated at the site of induction through the expression of an array of homing molecules such as integrins, addressins, and chemokine receptors (14).…”

LocalSalmonellaimmunostimulation recruits vaccine-specific CD8 T cells and increases regression of bladder tumor

“…3 Bone marrow-derived dendritic cells (BMDCs) were isolated using bone marrow cells collected from tibias and femurs of female C57BL/6 mice and cultured in the presence of 150 U/mL recombinant granulocyte-macrophagecolony stimulating-factor (R and D Systems). 2 IFN-g ELISPOT assay IFN-g ELISPOT assays were performed as described 45 A or 1 instillation in B), or s.c. E7 vaccine alone (white diamonds) or followed by Ty21a (black squares, 3 doses in A and 1 dose in B). Mouse survival curves are shown for each treatment (A and B).…”

“…1 This can be improved by using appropriate vaccine administration routes, allowing targeting of relevant tumor sites through specific mucosal homing or cancer site retention programs. [2][3][4][5] An alternative approach, irrespective of the immunization route, is to enhance T-cell attraction to the tumor site through the local application of selected chemokines 6 or Toll-like receptor (TLR) agonists that are able to modify the expression of selectins, integrins, chemokines, and chemokine receptors. 7,8 Along this line, we recently reported that intravaginal (IVAG) administration of CpG (a TLR-9 agonist) resulted in the accumulation of CD8 T cells co-expressing CCR5 and CXCR3 chemokine receptors and E-selectin ligands (ESL), most probably through CpG-induced expression of CCL5, CXCL9, CXCL10, CXCL11, and/or E-selectin 9 .…”

Mucosal vaccines

“…169 In contrast, studies conducted by the Nardelli-Haefliger's group showed that parenteral immunization was more effective than mucosal immunization to control the growth of intrauterine tumor. 170 In this model, it is possible that other effectors, such as antibodies, play a role in the tumor rejection, as the phenomenon of compartmentalization is less evident in humoral responses. Furthermore, the intravaginal immunization route is generally less effective in inducing effector T cell responses, which can be related to the low presence of lymphoid structures in the vagina, since the majority of structures are diffuse clusters of immune cells, and also to the hormonal dependence of this route.…”