Mesothelin-specific CD8+ T Cell Responses Provide Evidence of In Vivo Cross-Priming by Antigen-Presenting Cells in Vaccinated Pancreatic Cancer Patients

Abstract

Tumor-specific CD8+ T cells can potentially be activated by two distinct mechanisms of major histocompatibility complex class I–restricted antigen presentation as follows: direct presentation by tumor cells themselves or indirect presentation by professional antigen-presenting cells (APCs). However, controversy still exists as to whether indirect presentation (the cross-priming mechanism) can contribute to effective in vivo priming of tumor-specific CD8+ T cells that are capable of eradicating cancer in patients. A clinical trial of vaccination with granulocyte macrophage–colony stimulating factor–transduced pancreatic cancer lines was designed to test whether cross-presentation by locally recruited APCs can activate pancreatic tumor-specific CD8+ T cells. Previously, we reported postvaccination delayed-type hypersensitivity (DTH) responses to autologous tumor in 3 out of 14 treated patients. Mesothelin is an antigen demonstrated previously by gene expression profiling to be up-regulated in most pancreatic cancers. We report here the consistent induction of CD8+ T cell responses to multiple HLA-A2, A3, and A24-restricted mesothelin epitopes exclusively in the three patients with vaccine-induced DTH responses. Importantly, neither of the vaccinating pancreatic cancer cell lines expressed HLA-A2, A3, or A24. These results provide the first direct evidence that CD8 T cell responses can be generated via cross-presentation by an immunotherapy approach designed to recruit APCs to the vaccination site.

Enhancement of antitumor immunity by low-dose total body irradiationis associated with selectively decreasing the proportion and number of T regulatorycells

“…The heightened vaccine-based antitumor immune response in irradiated hosts was associated with tumor regression and prolonged survival of mice. It had previously been thought that some cytotoxic agents, such as cyclophosphamide, might enhance the efficacy of adoptively transferred immunotherapy by augmenting the engraftment of adoptively transferred tumor-reactive effector T cells, [11][12][13] possibly by creating space. 1, 14 However, in our study, vaccination after irradiation without adoptive transfer yielded similar results, indicating that a self-reconstituted host immune system is reliable for antigen stimulation.…”

In vivo depletion of DC impairs the anti‐tumor effect of agonistic anti‐CD137 mAb

“…Experimentation in BM chimeric mice with differential expression of antigen-presenting molecules and in humans vaccinated with allogeneic tumor cells has demonstrated that the ability to cross-present cell-associated antigens is restricted to BM-derived APC [24,25]. Several groups have investigated the identity of the BM-derived APC involved in MHC class I-restricted presentation of exogenous antigens.…”

“…It is still unresolved whether cross-presentation or direct presentation is the relevant mechanism governing tumor immunity [20,21]. Although some studies have suggested that the two processes act as redundant non-mutually exclusive mechanisms [22], other authors have proposed cross-presentation to be the major mechanism for the activation of naïve CD8 1 T cells [23].Experimentation in BM chimeric mice with differential expression of antigen-presenting molecules and in humans vaccinated with allogeneic tumor cells has demonstrated that the ability to cross-present cell-associated antigens is restricted to BM-derived APC [24,25]. Several groups have investigated the identity of the BM-derived APC involved in MHC class I-restricted presentation of exogenous antigens.…”

The Role of Mesothelin in Pancreatic Cancer

“…Yet another toxin insertion approach used a a biodegradable nanoparticulate delivery system targeted specifically to mesothelin-overxpressing cell lines to deliver diphtheria toxin DNA, which effectively inhibited protein translation of targeted cells in vitro 38 . specific CD4 + and CD8 + T cells were generated from peripheral blood lymphocytes of 50% of patients with pancreatic cancer, up from only 20% of healthy individuals 27 , and another study showed consistent induction of CD8 + T cell responses to multiple MSLN epitopes in a small number of patients 40 . A study by Yokokawa et al sought to define additional MSLN epitotpes capable of more efficiently activating T cells to lyse tumors 10 .…”