Abstract
Increasing evidence argues that the success of an anticancer treatment may rely on immunoadjuvant side effects including the induction of immunogenic tumor cell death. Based on the assumption that this death mechanism is a similar prerequisite for the efficacy of an active immunotherapy using killed tumor cells, we examined a vaccination strategy using dendritic cells (DC) loaded with apoptotic and necrotic cell bodies derived from autologous tumors. Using this approach, clinical and immunologic responses were achieved in 6 of 18 patients with relapsed indolent non-Hodgkin's lymphoma (NHL). The present report illustrates an impaired ability of the neoplastic cells used to vaccinate nonresponders to undergo immunogenic death on exposure to a cell death protocol based on heat shock, γ-ray, and UVC ray. Interestingly, when compared with doxorubicin, this treatment increased surface translocation of calreticulin and cellular release of high-mobility group box 1 and ATP in histologically distinct NHL cell lines. In contrast, treated lymphoma cells from responders displayed higher amounts of calreticulin and heat shock protein 90 (HSP90) compared with those from nonresponders and boosted the production of specific antibodies when loaded into DCs for vaccination. Accordingly, the extent of calreticulin and HSP90 surface expression in the DC antigenic cargo was significantly associated with the clinical and immunologic responses achieved. Our results indicate that a positive clinical effect is obtained when immunogenically killed autologous neoplastic cells are used for the generation of a DC-based vaccine. Therapeutic improvements may thus be accomplished by circumventing the tumor-impaired ability to undergo immunogenic death and prime the antitumor immune response.
Highlights
Vaccination with cancer cells treated ex vivo with antracyclines or oxaliplatin or ionizing radiation protects mice against a subsequent challenge with live tumor cells [1,2,3,4]
Our study confirms in a human setting recent findings obtained in mice concerning the possibility of inducing immunogenic death in cancer cells to provide a reliable source of antigens for antitumor vaccination [1]
We found that when three human non–Hodgkin's lymphoma (NHL) cell lines representing low, intermediate- and high-grade lymphomas were treated with heat shock (HS), γ, and UVC, they displayed all of the key features required to trigger a dendritic cells (DC)-mediated antitumor immune response, including the plasma membrane translocation of CRT and HSPs and the release of high-mobility group box 1 (HMGB1) and ATP [8, 21]
Summary
Vaccination with cancer cells treated ex vivo with antracyclines or oxaliplatin or ionizing radiation protects mice against a subsequent challenge with live tumor cells [1,2,3,4]. The immunizing properties of killed tumor cells depends on the ability of a cytotoxic agent to render their death immunogenic so that the immune system can be . Gandini Medical Oncology, Bone Marrow Transplantation Unit, 2Molecular Targeting Unit, 3Proteomics Laboratory, Department of Experimental Oncology, 4Pathology Unit, and 5Immunotherapy and Gene Therapy Unit, Department of Experimental Oncology, Fondazione Istituti di Ricovero e Cura a Carattere Scientifico, Istituto Nazionale per lo Studio e la Cura dei Tumori; and 6School of Medical Oncology, University of Milan, Milan, Italy. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).
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