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1.
Cell Death Differ ; 23(6): 1004-15, 2016 06.
Article in English | MEDLINE | ID: mdl-27082453

ABSTRACT

Intratumoral immunotherapies aim at reducing local immunosuppression, as well as reinstating and enhancing systemic anticancer T-cell functions, without inducing side effects. LTX-315 is a first-in-class oncolytic peptide-based local immunotherapy that meets these criteria by inducing a type of malignant cell death that elicits anticancer immune responses. Here, we show that LTX-315 rapidly reprograms the tumor microenvironment by decreasing the local abundance of immunosuppressive Tregs and myeloid-derived suppressor cells and by increasing the frequency of polyfunctional T helper type 1/type 1 cytotoxic T cells with a concomitant increase in cytotoxic T-lymphocyte antigen-4 (CTLA4) and drop in PD-1 expression levels. Logically, in tumors that were resistant to intratumoral or systemic CTLA4 blockade, subsequent local inoculation of LTX-315 cured the animals or caused tumor regressions with abscopal effects. This synergistic interaction between CTLA4 blockade and LTX-315 was reduced upon blockade of the ß-chain of the interleukin-2 receptor (CD122). This preclinical study provides a strong rationale for administering the oncolytic peptide LTX-315 to patients who are receiving treatment with the CTLA4 blocking antibody ipilimumab.


Subject(s)
CTLA-4 Antigen/metabolism , Neoplasms/drug therapy , Oligopeptides/therapeutic use , Animals , Antibodies, Monoclonal/immunology , Antibodies, Monoclonal/therapeutic use , CD4-Positive T-Lymphocytes/cytology , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/metabolism , CD8-Positive T-Lymphocytes/cytology , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/metabolism , CTLA-4 Antigen/immunology , Cell Line, Tumor , Chemokine CXCL10/analysis , Cytokines/metabolism , Drug Resistance, Neoplasm , HMGB1 Protein/analysis , Interleukin-2 Receptor beta Subunit/metabolism , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Knockout , Neoplasms/mortality , Neoplasms/therapy , Programmed Cell Death 1 Receptor/metabolism , Receptor, Interferon alpha-beta/deficiency , Receptor, Interferon alpha-beta/genetics , Toll-Like Receptor 4/deficiency , Toll-Like Receptor 4/genetics , Transplantation, Homologous
2.
Cell Death Differ ; 21(1): 50-8, 2014 Jan.
Article in English | MEDLINE | ID: mdl-23744294

ABSTRACT

Immunogenic cell death induced by cytotoxic compounds contributes to the success of selected chemotherapies by eliciting a protective anticancer immune response, which is mediated by CD4(+) and CD8(+) T cells producing interferon-γ. In many instances, cancer progression is associated with high titers of tumor-specific antibodies, which become detectable in the serum, but whose functional relevance is elusive. Here, we explored the role of humoral immune responses in the anticancer efficacy of anthracyclines. Chemotherapy reduced the number of tumor-infiltrating B cells, and failed to promote humoral responses against immunodominant tumor antigens. Although anthracycline-based anticancer chemotherapies failed in T cell-deficient mice, they successfully reduced the growth of cancers developing in mice lacking B lymphocytes (due to the injection of a B-cell-depleting anti-CD20 antibody), immunoglobulins (Igs) or Ig receptors (Fc receptor) due to genetic manipulations. These results suggest that the humoral arm of antitumor immunity is dispensable for the immune-dependent therapeutic effect of anthracyclines against mouse sarcoma. In addition, we show here that the titers of IgA and IgG antibodies directed against an autoantigen appearing at the cell surface of tumor cells post chemotherapy (calreticulin, CRT) did not significantly increase in patients treated with anthracyclines, and that anti-CRT antibodies had no prognostic or predictive significance. Collectively, our data indicate that humoral anticancer immune responses differ from cellular responses in, thus far, that they do not contribute to the success of anthracycline-mediated anticancer therapies in human breast cancers and mouse sarcomas.


Subject(s)
Anthracyclines/therapeutic use , Antineoplastic Agents/therapeutic use , Breast Neoplasms/drug therapy , Immunity, Humoral , Animals , Anthracyclines/toxicity , Antibodies/immunology , Antibodies/pharmacology , Antineoplastic Agents/toxicity , Apoptosis/drug effects , B-Lymphocytes/drug effects , B-Lymphocytes/immunology , Breast Neoplasms/immunology , Breast Neoplasms/pathology , Calreticulin/immunology , Calreticulin/metabolism , Cell Line, Tumor , Female , Humans , Mice , Mice, Inbred C57BL , Middle Aged , Receptors, Fc/metabolism , Sarcoma/drug therapy , T-Lymphocytes, Cytotoxic/immunology
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