Therapy for minimal residual tumor disease: β‐Galactosylceramide inhibits the growth of recurrent HPV16‐associated neoplasms after surgery and chemotherapy

Abstract

Natural killer T (NKT) cells are potent modulators of antitumor immunity. Their protective effects can be achieved upon their activation by glycolipid ligands presented in the context of the CD1d molecule. These CD1d-binding glycolipid antigens have been described as potent therapeutic agents against tumors, infections, as well as autoimmune diseases. Immunoregulatory and therapeutic effects of glycolipid ligands depend on their structure and modes of administration. Therefore, more studies are needed for optimization of the particular therapeutic settings. This study was focused on the tumor-inhibitory effects of 12 carbon acyl chain b-galactosyl ceramide (C12 b-D-Galactosyl Ceramide; b-GalCer(C12)) on the growth of human papillomavirus type 16 (HPV16)-associated neoplasms transplanted in syngeneic mice. Treatment of tumor-bearing mice with b-GalCer(C12) 3-14 days after tumor cell transplantation significantly inhibited the growth of the major histocompatability complex (MHC) Class I-positive (TC-1), as well as MHC Class I-deficient (TC-1/A9) HPV16-asssociated tumors. Moreover, administration of b-GalCer(C12) after surgical removal of TC-1 tumors inhibited the growth of tumor recurrences. Similar results were obtained in the treatment of tumors after chemotherapy. b-GalCer(C12) treatment turned out to be also synergistic with immunotherapy based on administration of IL-12-producing cellular vaccines. These results suggest that bGalCer(C12), whose antitumor effects have so far not been studied in detail, can be effective for the treatment of minimal residual tumor disease as well as an adjuvant for cancer immunotherapy.Natural killer T (NKT) cells characterized by cell surface expression of T-cell and NK-cell receptors are important immune regulators that can either promote or suppress antitumor and anti-infection immunity, as well as autoimmunity.1-3 Antitumor activities of NKT cells have mainly been attributed to their Type I (expressing Va14Ja18 and Va24Ja18 TCRa in mice and humans, respectively) that recognize glycolipid antigens in the context of major histocompatability complex (MHC) Class I-like molecule CD1d. NKT cells can be modulated by analogues of their natural, so far poorly characterized, glycolipid ligands. Their specific effects, e.g. induction of cytokine production, NKT cell expansion and activation of a variety of immune cells, as well as NKT cell receptor downregulation and induction of NKT cell anergy strongly depend on their structure and mode of administration. 4,5 So far, most in vivo studies investigating antitumor potential of NKT cell-activating glycolipids have been focused on a-galactosylceramide, originally described as an antitumor drug.6 Much less is known about the antitumor effects of b-anomers. Several clinical studies were performed in which the patients were given either free a-galactosylceramide (a-GalCer) or dendritic cells pulsed with a-GalCer.7-9 In these trials, NKT cell activation/expansion and cytokine production was observed in the treated patients. However, the immun...

Activities of stromal and immune cells in HPV-related cancers

“…Its activation occurs through the recognition of CD1d molecules by TCR, and thus, is able to kill tumor cells [ 126 ] and induce the maturation of DC that expresses CD40L (activated stage) [ 127 ]. CD1d ligands (α-, β-galactosylceramide) have demonstrated protector activity against cancer caused by HPV16 [ 128 ] and have been the first to be used therapeutically as adjuvant in DNA vaccine against this viral type [ 129 ]. In combination with TLR agonists, these ligands can improve vaccine strategies: the delivering of an HPV16 E7 vaccine together with α-galactosylceramide and MPL, a TLR4 agonist, caused an increase in CTL response, lymphocyte proliferation, IFN-γ synthesis and reduction of tumor volume in a C57BL/6 mice tumor model [ 130 ].…”

Role of Innate Immunity against Human Papillomavirus (HPV) Infections and Effect of Adjuvants in Promoting Specific Immune Response

“…In a mouse model, with TC-1 tumor cells (expressing E6 and E7), the number of E7-specific CD8+ T-cells was found to be increased when α-GalCer was administered as an adjuvant in addition to DNA vaccine encoding the HPV16 E7 oncoprotein; in addition, this treatment generated potent anti TC-1 tumor effects [60] (Table 1). Administration of β-GalCer(C12) without HPV antigen was also able to inhibit the growth of TC-1 at the early stages of tumor progression [61] (Table 1). …”

The role of immune cell subpopulations in the growth and rejection of TC‑1/A9 tumors in novel mouse strains differing in the H2‑D haplotype and NKC domain

“…Of note, the expression of asialo-GM1 is not strictly confined to NK cells among hematopoietic cells and is detected on a subpopulation of NKT, CD8 + T, and γδ T cells and some activated form of CD4 + T cells, macrophages, and eosinophils under certain experimental conditions. At least NKT cells, characterized by expression of T cell and NK cell receptors, are important immune regulators that can either promote or suppress antitumor immunity and could play a role in the growth and regression of TC-1/A9 tumors ( 19 – 21 ). Nevertheless, anti-asialo GM1-mediated NK cell depletion still remains a powerful tool to analyze the in vivo functions of NK cells ( 22 ).…”