A heat-shocked melanoma cell lysate vaccine enhances tumor infiltration by prototypic effector T cells inhibiting tumor growth
Background Immune checkpoint blocker (ICB) therapy has shown survival benefits for some patients with cancer. Nevertheless, many individuals remain refractory or acquire resistance to treatment, motivating the exploration of complementary immunotherapies. Accordingly, cancer vaccines offer an attrac...
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BMJ Publishing Group
2020-10-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/8/2/e000999.full |
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| author | María Alejandra Gleisner Cristián Pereda Andrés Tittarelli Mariela Navarrete Camila Fuentes Ignacio Ávalos Fabian Tempio Juan Pablo Araya María Inés Becker Fermín Eduardo González Mercedes Natalia López Flavio Salazar-Onfray |
| author_facet | María Alejandra Gleisner Cristián Pereda Andrés Tittarelli Mariela Navarrete Camila Fuentes Ignacio Ávalos Fabian Tempio Juan Pablo Araya María Inés Becker Fermín Eduardo González Mercedes Natalia López Flavio Salazar-Onfray |
| author_sort | María Alejandra Gleisner |
| collection | DOAJ |
| description | Background Immune checkpoint blocker (ICB) therapy has shown survival benefits for some patients with cancer. Nevertheless, many individuals remain refractory or acquire resistance to treatment, motivating the exploration of complementary immunotherapies. Accordingly, cancer vaccines offer an attractive alternative. Optimal delivery of multiple tumor-associated antigens combined with potent adjuvants seems to be crucial for vaccine effectiveness.Methods Here, a prototype for a generic melanoma vaccine, named TRIMELVax, was tested using B16F10 mouse melanoma model. This vaccine is made of heat shock-treated tumor cell lysates combined with the Concholepas concholepas hemocyanin as adjuvant.Results While B16F10 lysate provides appropriate melanoma-associated antigens, both a generic human melanoma cell lysate and hemocyanin adjuvant contributes with danger signals promoting conventional dendritic type 1 cells (cDC1), activation, phagocytosis and effective antigen cross-presentation. TRIMELVax inhibited tumor growth and increased mice survival, inducing cellular and humoral immune responses. Furthermore, this vaccine generated an increased frequency of intratumor cDC1s but not conventional type 2 dendritic cells (cDC2s). Augmented infiltration of CD3+, CD4+ and CD8+ T cells was also observed, compared with anti-programmed cell death protein 1 (PD-1) monotherapy, while TRIMELVax/anti-PD-1 combination generated higher tumor infiltration of CD4+ T cells. Moreover, TRIMELVax promoted an augmented proportion of PD-1lo CD8+ T cells in tumors, a phenotype associated with prototypic effector cells required for tumor growth control, preventing dysfunctional T-cell accumulation.Conclusions The therapeutic vaccine TRIMELVax efficiently controls the weakly immunogenic and aggressive B16F10 melanoma tumor growth, prolonging tumor-bearing mice survival even in the absence of ICB. The strong immunogenicity shown by TRIMELVax encourages clinical studies in patients with melanoma. |
| format | Article |
| id | doaj-art-28c908f8ce38455c8c9cfa54e97678c0 |
| institution | Kabale University |
| issn | 2051-1426 |
| language | English |
| publishDate | 2020-10-01 |
| publisher | BMJ Publishing Group |
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| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-28c908f8ce38455c8c9cfa54e97678c02024-11-10T13:40:09ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262020-10-018210.1136/jitc-2020-000999A heat-shocked melanoma cell lysate vaccine enhances tumor infiltration by prototypic effector T cells inhibiting tumor growthMaría Alejandra Gleisner0Cristián Pereda1Andrés Tittarelli2Mariela Navarrete3Camila Fuentes4Ignacio Ávalos5Fabian Tempio6Juan Pablo Araya7María Inés Becker8Fermín Eduardo González9Mercedes Natalia López10Flavio Salazar-Onfray112 Millennium Institute on Immunology and Immunotherapy, Faculty of Medicine, Universidad de Chile, Santiago, Chile1 Disciplinary Program of Immunology, Institute of Biomedical Sciences, Faculty of Medicine, Universidad de Chile, Santiago, Chile2 Millennium Institute on Immunology and Immunotherapy, Faculty of Medicine, Universidad de Chile, Santiago, Chile1 Disciplinary Program of Immunology, Institute of Biomedical Sciences, Faculty of Medicine, Universidad de Chile, Santiago, Chile1 Disciplinary Program of Immunology, Institute of Biomedical Sciences, Faculty of Medicine, Universidad de Chile, Santiago, Chile1 Disciplinary Program of Immunology, Institute of Biomedical Sciences, Faculty of Medicine, Universidad de Chile, Santiago, Chile2 Millennium Institute on Immunology and Immunotherapy, Faculty of Medicine, Universidad de Chile, Santiago, Chile1 Disciplinary Program of Immunology, Institute of Biomedical Sciences, Faculty of Medicine, Universidad de Chile, Santiago, Chile4 Fundación Ciencia y Tecnología para el Desarrollo (FUCITED), Avenida Eduardo Castillo Velasco 2902, Santiago, Chile2 Millennium Institute on Immunology and Immunotherapy, Faculty of Medicine, Universidad de Chile, Santiago, Chile1 Disciplinary Program of Immunology, Institute of Biomedical Sciences, Faculty of Medicine, Universidad de Chile, Santiago, Chile1 Disciplinary Program of Immunology, Institute of Biomedical Sciences, Faculty of Medicine, Universidad de Chile, Santiago, ChileBackground Immune checkpoint blocker (ICB) therapy has shown survival benefits for some patients with cancer. Nevertheless, many individuals remain refractory or acquire resistance to treatment, motivating the exploration of complementary immunotherapies. Accordingly, cancer vaccines offer an attractive alternative. Optimal delivery of multiple tumor-associated antigens combined with potent adjuvants seems to be crucial for vaccine effectiveness.Methods Here, a prototype for a generic melanoma vaccine, named TRIMELVax, was tested using B16F10 mouse melanoma model. This vaccine is made of heat shock-treated tumor cell lysates combined with the Concholepas concholepas hemocyanin as adjuvant.Results While B16F10 lysate provides appropriate melanoma-associated antigens, both a generic human melanoma cell lysate and hemocyanin adjuvant contributes with danger signals promoting conventional dendritic type 1 cells (cDC1), activation, phagocytosis and effective antigen cross-presentation. TRIMELVax inhibited tumor growth and increased mice survival, inducing cellular and humoral immune responses. Furthermore, this vaccine generated an increased frequency of intratumor cDC1s but not conventional type 2 dendritic cells (cDC2s). Augmented infiltration of CD3+, CD4+ and CD8+ T cells was also observed, compared with anti-programmed cell death protein 1 (PD-1) monotherapy, while TRIMELVax/anti-PD-1 combination generated higher tumor infiltration of CD4+ T cells. Moreover, TRIMELVax promoted an augmented proportion of PD-1lo CD8+ T cells in tumors, a phenotype associated with prototypic effector cells required for tumor growth control, preventing dysfunctional T-cell accumulation.Conclusions The therapeutic vaccine TRIMELVax efficiently controls the weakly immunogenic and aggressive B16F10 melanoma tumor growth, prolonging tumor-bearing mice survival even in the absence of ICB. The strong immunogenicity shown by TRIMELVax encourages clinical studies in patients with melanoma.https://jitc.bmj.com/content/8/2/e000999.full |
| spellingShingle | María Alejandra Gleisner Cristián Pereda Andrés Tittarelli Mariela Navarrete Camila Fuentes Ignacio Ávalos Fabian Tempio Juan Pablo Araya María Inés Becker Fermín Eduardo González Mercedes Natalia López Flavio Salazar-Onfray A heat-shocked melanoma cell lysate vaccine enhances tumor infiltration by prototypic effector T cells inhibiting tumor growth Journal for ImmunoTherapy of Cancer |
| title | A heat-shocked melanoma cell lysate vaccine enhances tumor infiltration by prototypic effector T cells inhibiting tumor growth |
| title_full | A heat-shocked melanoma cell lysate vaccine enhances tumor infiltration by prototypic effector T cells inhibiting tumor growth |
| title_fullStr | A heat-shocked melanoma cell lysate vaccine enhances tumor infiltration by prototypic effector T cells inhibiting tumor growth |
| title_full_unstemmed | A heat-shocked melanoma cell lysate vaccine enhances tumor infiltration by prototypic effector T cells inhibiting tumor growth |
| title_short | A heat-shocked melanoma cell lysate vaccine enhances tumor infiltration by prototypic effector T cells inhibiting tumor growth |
| title_sort | heat shocked melanoma cell lysate vaccine enhances tumor infiltration by prototypic effector t cells inhibiting tumor growth |
| url | https://jitc.bmj.com/content/8/2/e000999.full |
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