Molecular requirements for CD8-mediated rejection of a MUC1-expressing pancreatic carcinoma: implications for tumor vaccines

Abstract

Previous studies have indicated that different effector cells are required to eliminate MUC1-expressing tumors derived from different organ sites and that different vaccine strategies may be necessary to generate these two different MUC1-specific immune responses. In this study, we characterized molecular components that are required to produce immune responses that eliminate Panc02.MUC1 tumors in vivo by utilizing mice genetically deficient in molecules related to immunity. A parallel study has been reported for a B16.MUC1 tumor model. We confirmed that a CD8(+) effector cell was required to eliminate MUC1-expressing Panc02 tumors, and demonstrated that T cells expressing TCR-alpha/beta and co-stimulation through CD28 and CD40:CD40L interactions played critical roles during the initiation of the anti-Panc02.MUC1 immune response. TCR-alpha/beta(+) cells were required to eliminate Panc02.MUC1 tumors, while TCR-gamma/delta(+) cells played a suppressive non-MUC1-specific role in anti-Panc02 tumor immunity. Type 1 cytokine interferon-gamma (IFN-gamma), but not interleukin-12 (IL-12), was essential for eliminating MUC1-expressing tumors, while neither IL-4 nor IL-10 (type 2 cytokines) were required for tumor rejection. In vitro studies demonstrated that IFN-gamma upregulated MHC class I, but not MHC class II, on Panc02.MUC1 tumor cells. Surprisingly, both perforin and FasL played unique roles during the effector phase of immunity to Panc02.MUC1, while lymphotoxin-alpha, but not TNFR-1, was required for immunity against Panc02.MUC1 tumors. The findings presented here and in parallel studies of B16.MUC1 immunity clearly demonstrate that different effector cells and cytolytic mechanisms are required to eliminate MUC1-expressing tumors derived from different organ sites, and provide insight into the immune components required to eliminate tumors expressing the same antigen but derived from different tissues.

The Antitumor and Immunoadjuvant Effects of IFN-α in Combination with Recombinant Poxvirus Vaccines

“…These findings are consistent with the work of Sivinski et al (43) who reported a significant role for these cell populations in generating antitumor immunity against parental Panc02 tumors. The absence of synergy between IFN-α and CEA vaccine in mice with Panc02.CEA tumors was surprising considering the efficacy of the individual treatments and the synergistic effects of this combination in mice with MC38.CEA tumors.…”

“…Our antibody blockade experiments support a role of CD80 expression in mediating antitumor immunity. Costimulation through CD80 is likely an important mediator of adaptive immunity in the Panc02 system because CD28 -/- mice show markedly reduced survival following a challenge with the parental Panc02 cell line (43). The role of CD80 in mediating the interaction between tumor and the immune system is complex, however, because low CD80 expression is reported to contribute to tumor escape through preferential engagement of CD152 (CTLA-4) on T cells (44).…”

Decreased Total Lymphocyte Counts in Pancreatic Cancer: An Index of Adverse Outcome

“…12,16,17,[33][34][35][36] Interestingly, lymphocytes were not found to infiltrate the pancreatic tumor mass, being preferentially localized in the peripheral stroma. Furthermore, in a subset of our patients with PC, tumor infiltrating lymphocyte subsets were also evaluated.…”

A Unique Mucin Immunoenhancing Peptide with Antitumor Properties

“…The alteration of MUC1 in neoplasia makes it an ideal tumor antigen for use both diagnostically and in therapy, and several studies highlight the potential of the MUC1 molecule in the development of tumor-antigen-specific vaccines (12)(13)(14).…”