An NKT-mediated autologous vaccine generates CD4 T-cell–dependent potent antilymphoma immunity

Abstract

Relapses occurring in most patients with lymphoma after antibody or chemotherapy highlight a need for effective vaccination approaches. Autologous tumors are ideal sources of patient-specific tumor antigens for vaccines; however, their poor immunogenicity has been a major obstacle in practice. Natural killer T (NKT) cells have recently emerged as crucial regulators of autoimmunity and tumor immunosurveillance. Here, we show that an autologous lymphoma vaccine that activates NKT cells generated tumorspecific protective immunity in experimental mice. Single vaccination with ␣-galactosylceramide (␣GC)-loaded A20 lymphoma cells elicited effective antitumor immunity against tumor challenge. This vaccination strategy also induced significant tumor regression in A20-bearing mice. Importantly, the survivors from primary tumor inoculation were all resistant to tumor rechallenge, indicative of established adaptive memory immunity. Depletion as well as adoptive transfer studies revealed an exclusive role of conventional CD4 ؉ but not CD8 ؉ T cells in mediating antitumor immunity. In addition, we found normal hematopoietic compartments in the vaccinated mice. Therefore, NKT ligand-loaded lymphoma elicits long-lasting and effective antitumor immunity, which can be further developed as patient-and tumor-specific immunotherapy against human lymphomas. IntroductionInduction of tumor-specific adaptive immunity in individual patients with cancer is an ideal approach because its selectivity and memory for the same tumors eventually prevent the recurrence of residual tumors after conventional therapies. Among current strategies to elicit immunity against tumor-associated antigen (TAA), using autologous tumor as a source of TAAs is an attractive strategy since specific TAAs have not been identified for most tumors. Moreover, vaccinations with autologous tumors can provide a wide range of "polyvalent" TAAs, and thus defining TAAs in each individual is not necessary for immunotherapy. Because of their antigen-presenting capacity, vaccination with autologous tumors of B-cell origin may be particularly useful for treating B-cell lymphomas. 1 Since these tumors are typically poorly immunogenic by themselves, many approaches have sought to improve immunogenicity, such as transducing cytokines or costimulators into tumor cells 2-6 as well as pulsing dendritic cells (DCs) with tumors. 7 These strategies have been shown to be successful at certain degrees to elicit antitumor activities and memory via activation of TAA-specific T cells. Nevertheless, technical and financial challenges, as well as safety issues for genetic modification or DC presentation, are major obstacles to their widespread use in clinical settings. Thus, development of a convenient and practical vaccine strategy with potent efficacy will be beneficial.Natural killer T (NKT) cells recognize glycolipid antigens on a nonclassical major histocompatibility complex (MHC) molecule, CD1d. Although they represent minor population in the immune system, NKT cells have become crucia...

An autologous leukemia cell vaccine prevents murine acute leukemia relapse after cytarabine treatment

“…Because this chemotherapeutic agent is in routine clinical use for leukemia induction and consolidation, 67,68 these results are of particular relevance clinically. 27,29 Our results support a previous in vivo study with C1498 in which mice treated with a granulocyte macrophage colony-stimulating factor-secreting irradiated cell vaccine 5 or 7 days after cytarabine treatment were protected against the development of leukemia, despite transient development of severe neutropenia and lymphopenia following chemotherapy. 59 We have demonstrated successful combination of immunotherapy after chemotherapy pretreatment of leukemic mice and have shown that cytarabine alone did not induce changes to the immune environment that could be detected by day 20.…”

“…Interactions between DCs and NKT cells promote CD40 signaling, leading to DC activation, which increases the capacity of DCs to stimulate peptide-specific T cells. 23,24 Significantly, vaccines comprising irradiated tumor cells pulsed with a-GalCer have been shown to be effective in murine models of hematopoietic malignancies, including acute myeloid leukemia (AML) and acute lymphoid leukemia, 23,27,28 and in other malignancies. 25,27,29 Cancer-associated immunosuppression can present a significant barrier to effective vaccine-based immunotherapy.…”

“…23,24 Significantly, vaccines comprising irradiated tumor cells pulsed with a-GalCer have been shown to be effective in murine models of hematopoietic malignancies, including acute myeloid leukemia (AML) and acute lymphoid leukemia, 23,27,28 and in other malignancies. 25,27,29 Cancer-associated immunosuppression can present a significant barrier to effective vaccine-based immunotherapy. 30 AML generates an immunosuppressive environment, 31,32 characterized by impaired DC function 33 and increased levels of regulatory T cells (Tregs).…”

Immunosuppressive Myeloid-Derived Suppressor Cells Can Be Converted into Immunogenic APCs with the Help of Activated NKT Cells: An Alternative Cell-Based Antitumor Vaccine

“…␣GalCer, the ligand of type I NKT cells, has been widely used as an adjuvant to enhance antitumor immunity, not only as a free form (34) but also as a loaded form onto various CD1d-expressing cells, including DCs (19,20), B cells (21,22), or tumor cells (35)(36)(37). Paradoxically, however, NKT cells have also been reported to suppress tumor immunosurveillance (38,39) rather than induce protective immunity (40,41) in several tumor models.…”

Adoptive cellular immunotherapy for childhood malignancies

“…NKT cells are appreciated for their ability to regulate autoimmunity and tumor surveillance and a role for selectively activating NKT in vivo is beginning to be explored. 67,68 Adoptive cellular immunotherapy for melanoma While melanoma is generally not a pediatric malignancy, the infusions of tumor-specific T cells has resulted in seven important principles that can be generalized for the field of adoptive immunotherapy for pediatric tumors. (i) The first observation is that autologous tumor-specific T cells can be identified in patients with cancer.…”