Baculovirus-Infected Insect Cells Expressing Peptide-MHC Complexes Elicit Protective Antitumor Immunity

Abstract

Evaluation of T cell responses to tumor- and pathogen-derived peptides in preclinical models is necessary to define the characteristics of efficacious peptide vaccines. We show in this study that vaccination with insect cells infected with baculoviruses expressing MHC class I linked to tumor peptide mimotopes results in expansion of functional peptide-specific CD8+ T cells that protect mice from tumor challenge. Specific peptide mimotopes selected from peptide-MHC libraries encoded by baculoviruses can be tested using this vaccine approach. Unlike other vaccine strategies, this vaccine has the following advantages: peptides that are difficult to solublize can be easily characterized, bona fide peptides without synthesis artifacts are presented, and additional adjuvants are not required to generate peptide-specific responses. Priming of antitumor responses occurs within 3 days of vaccination and is optimal 1 wk after a second injection. After vaccination, the Ag-specific T cell response is similar in animals primed with either soluble or membrane-bound Ag, and CD11c+ dendritic cells increase expression of maturation markers and stimulate proliferation of specific T cells ex vivo. Thus, the mechanism of Ag presentation induced by this vaccine is consistent with cross-priming by dendritic cells. This straightforward approach will facilitate future analyses of T cells elicited by peptide mimotopes.

Peptide vaccines prevent tumor growth by activating T cells that respond to native tumor antigens

“…To determine how particular peptide variants generate effective T-cell responses, we have used the CT26 transplantable colon tumor model (11,13,26). The immunodominant antigen of CT26, gp70 423-431 (AH1), is derived from a self-antigen encoded by the genome of BALB/c mice (27).…”

Induction of antitumor immunity against mouse carcinoma by baculovirus-infected dendritic cells

“…The wild-type baculovirus-induced activation of host immunity and the inhibition of tumor growth are shown in Figure 1b; 20,21 however, mice treated with wild-type baculovirus also exhibited increased levels of serum ALT, AST and creatinine. We further investigated whether ALT, AST and creatinine increased in response to the administration of BVDCs.…”

“…Jordan et al demonstrated that vaccination with insect cells infected with recombinant, baculovirus-encoding peptide-MHC complexes generated peptide-specific cytotoxic T-cell responses and antitumor immunity. 20 We have previously described the induction of antitumor effects using wild-type baculovirus in a mouse model of hepatoma. 21 In particular, DCs were more potently infected by baculovirus than were other immune cells, and the DCs underwent activation and maturation.…”

Age-dependent tolerance to an endogenous tumor-associated antigen

“…For vaccination assays, 10 6 irradiated CT26-GM or CT26-βgal-GM cells were injected subcutaneously 16 or 14 and 7 days prior ex vivo examination or stimulation of splenocytes in culture as described [30]. Mice boosted with peptide received 5x10 6 Sf9 cells infected with recombinant baculovirus encoding peptide/H-2L d [34].…”

“…51 Cr-labeled MC57G-Ld cells were incubated with the AH1 or MCMV pp89 peptide (YPHFMPTNL). In vivo killing assays were performed as described [34]. Briefly, splenocytes were loaded with the AH1 (CFSE-high) or βgal (CFSE-low, TPHPARIGL) peptide and injected intravenously into vaccinated mice.…”