A pilot study on the immunogenicity of dendritic cell vaccination during adjuvant oxaliplatin/capecitabine chemotherapy in colon cancer patients

Contains fulltext : 87604.pdf (publisher's version ) (Closed access)BACKGROUND: Dendritic cell (DC) vaccination has been shown to induce anti-tumour immune responses in cancer patients, but so far its clinical efficacy is limited. Recent evidence supports an immunogenic effect of cytotoxic chemotherapy. Pre-clinical data indicate that the combination of chemotherapy and immunotherapy may result in an enhanced anti-cancer activity. Most studies have focused on the immunogenic aspect of chemotherapy-induced cell death, but only few studies have investigated the effect of chemotherapeutic agents on the effector lymphocytes of the immune system. METHODS: Here we investigated the effect of treatment with oxaliplatin and capecitabine on non-specific and specific DC vaccine-induced adaptive immune responses. Stage III colon cancer patients receiving standard adjuvant oxaliplatin/capecitabine chemotherapy were vaccinated at the same time with keyhole limpet haemocyanin (KLH) and carcinoembryonic antigen (CEA)-peptide pulsed DCs. RESULTS: In 4 out of 7 patients, functional CEA-specific T-cell responses were found at delayed type hypersensitivity (DTH) skin testing. In addition, we observed an enhanced non-specific T-cell reactivity upon oxaliplatin administration. KLH-specific T-cell responses remained unaffected by the chemotherapy, whereas B-cell responses were diminished. CONCLUSION: The results strongly support further testing of the combined use of specific anti-tumour vaccination with oxaliplatin-based chemotherapy

The Tumor-Immune Microenvironment and Response to Radiation Therapy

Chemotherapy and radiation therapy (RT) are standard therapeutic modalities for patients with cancer, including breast cancer. Historic studies examining tissue and cellular responses to RT have predominantly focused on damage caused to proliferating malignant cells leading to their death. However, there is increasing evidence that RT also leads to significant alterations in the tumor microenvironment, particularly with respect to effects on immune cells infiltrating tumors. This review focuses on tumor-associated immune cell responses following RT and discusses how immune responses may be modified to enhance durability and efficacy of RT

Immunogenic chemotherapy: discovery of a critical protein through proteomic analyses of tumor cells.

The aim of chemotherapy and radiotherapy is to eliminate tumor cells. While the outcomes of these cytotoxic treatments have previously been assigned to their direct effects on tumor cells, recent findings have shown that the host's immune system also contributes to the success of chemotherapeutic and radiotherapeutic regimens. The finding that some cytotoxic antitumor coumpounds such as anthracyclines were capable of triggering a potent T-cell-dependent antitumor response has prompted the search for molecular determinants responsible for the immunogenicity of anthracyclines. Proteomic analyses of anthracycline-treated tumor cells have recently revealed the critical involvement of calreticulin in mediating the immunogenicity of dying tumor cells. Here, we focused on the molecular study of immunogenic chemotherapy which led to the characterization of calreticulin as a critical protein in immunogenic cancer cell death

Immunogenic chemotherapy: discovery of a critical protein through proteomic analyses of tumor cells.

The aim of chemotherapy and radiotherapy is to eliminate tumor cells. While the outcomes of these cytotoxic treatments have previously been assigned to their direct effects on tumor cells, recent findings have shown that the host's immune system also contributes to the success of chemotherapeutic and radiotherapeutic regimens. The finding that some cytotoxic antitumor coumpounds such as anthracyclines were capable of triggering a potent T-cell-dependent antitumor response has prompted the search for molecular determinants responsible for the immunogenicity of anthracyclines. Proteomic analyses of anthracycline-treated tumor cells have recently revealed the critical involvement of calreticulin in mediating the immunogenicity of dying tumor cells. Here, we focused on the molecular study of immunogenic chemotherapy which led to the characterization of calreticulin as a critical protein in immunogenic cancer cell death

Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy.

Conventional cancer treatments rely on radiotherapy and chemotherapy. Such treatments supposedly mediate their effects via the direct elimination of tumor cells. Here we show that the success of some protocols for anticancer therapy depends on innate and adaptive antitumor immune responses. We describe in both mice and humans a previously unrecognized pathway for the activation of tumor antigen–specific T-cell immunity that involves secretion of the high-mobility-group box 1 (HMGB1) alarmin protein by dying tumor cells and the action of HMGB1 on Toll-like receptor 4 (TLR4) expressed by dendritic cells (DCs). During chemotherapy or radiotherapy, DCs require signaling through TLR4 and its adaptor MyD88 for efficient processing and cross-presentation of antigen from dying tumor cells. Patients with breast cancer who carry a TLR4 loss-of-function allele relapse more quickly after radiotherapy and chemotherapy than those carrying the normal TLR4 allele. These results delineate a clinically relevant immunoadjuvant pathway triggered by tumor cell death