Abstract
Cancer immunotherapy has shown promising results when combined with chemotherapy. Blocking CTLA-4 signaling by monoclonal antibody between cycles of chemotherapy may inhibit cancer cell repopulation and enhance the antitumoral immune reaction, thus improve the efficacy of chemotherapy in mesothelioma. The impact of CTLA-4 blockade on the early stage of tumor development was evaluated in a subcutaneous murine mesothelioma model. CTLA-4 blocking antibody was administered following each cycle of chemotherapy, and monotherapy was included as controls. Antitumor effect was evaluated by tumor growth delay and survival of the animals. Tumor cell repopulation was quantified by bromodeoxyuridine incorporation and Ki67 by immunohistochemistry and/or flow cytometry. In vitro cell killing was determined by classic chromium-released assay, and reverse transcription PCR (RT-PCR) was carried out to determine the gene expression of associated cytokines. Anti-CTLA-4 monoclonal antibody was able to inhibit tumor growth at early stage of tumor development. Antitumor effect was achieved by administration of CTLA-4 blockade between cycles of chemotherapy. Tumor cell repopulation during the intervals of cisplatin was inhibited by CTLA-4 blockade. Anti-CTLA-4 therapy gave rise to an increased number of CD4 and CD8 T cells infiltrating the tumor. RT-PCR showed that the gene expression of interleukin IL-2, IFN-γ, granzyme B, and perforin increased in the tumor milieu. Blockade of CTLA-4 signaling showed effective anticancer effect, correlating with inhibiting cancer cell repopulation between cycles of chemotherapy and upregulating tumor-infiltrating T lymphocytes, cytokines, and cytolytic enzymes in a murine mesothelioma model.
Highlights
Immunosuppressive components such as regulatory T cells (Treg), cyototoxic T lymphocyte-associated antigen-4 (CTLA-4), myeloid-derived suppressor cell (MDSC), and to some extent, tumor-infiltrating macrophages, play critical roles in tumor tolerance through a variety of mechanisms [1,2,3,4,5]
Administration of anti-CTLA-4 monoclonal antibody (mAb) during the intervals of cisplatin treatments slowed down tumor growth and prolonged survival of tumor-bearing mice
This effect was associated with significant inhibition of tumor cell repopulation between cycles of cisplatin treatments and significant increased in the total number of T cells and CD4þ, CD8þ T cells infiltrating into the tumor
Summary
Immunosuppressive components such as regulatory T cells (Treg), cyototoxic T lymphocyte-associated antigen-4 (CTLA-4), myeloid-derived suppressor cell (MDSC), and to some extent, tumor-infiltrating macrophages, play critical roles in tumor tolerance through a variety of mechanisms [1,2,3,4,5]. CD28 and their ligands B7-1 (CD80) and B7-2 (CD86) are critically important for the initial activation of naive T cells and regulation of the clonal composition of the responding repertoire following migration of activated dendritic cells to lymphoid organs [7,8,9] Taken together, these 4 molecules are perhaps the most important cofactors functioning in an immunologic cascade, providing signals that are crucial in T-cell activation and tolerance. Current understanding of CTLA-4 function in T-cell responses in vitro and in preclinical murine models made it possible to initiate application of CTLA-4 blockade as a novel immunotherapy for cancer [15, 16]. The impact of CTLA-4 blockade-based immunotherapy on cancer cell repopulation between cycles of chemotherapy has not been reported. We administered CTLA-4 blocking monoclonal antibody between cycles of cisplatin treatments in murine mesothelioma models to evaluate the benefit of antitumor effect
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