Vaccine Increases the Diversity and Activation of Intratumoral T Cells in the Context of Combination Immunotherapy
Resistance to immune checkpoint blockade therapy has spurred the development of novel combinations of drugs tailored to specific cancer types, including non-inflamed tumors with low T-cell infiltration. Cancer vaccines can potentially be utilized as part of these combination immunotherapies to enhan...
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-02-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/13/5/968 |
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| author | Lucas A. Horn Kristen Fousek Duane H. Hamilton James W. Hodge John A. Zebala Dean Y. Maeda Jeffrey Schlom Claudia Palena |
| author_facet | Lucas A. Horn Kristen Fousek Duane H. Hamilton James W. Hodge John A. Zebala Dean Y. Maeda Jeffrey Schlom Claudia Palena |
| author_sort | Lucas A. Horn |
| collection | DOAJ |
| description | Resistance to immune checkpoint blockade therapy has spurred the development of novel combinations of drugs tailored to specific cancer types, including non-inflamed tumors with low T-cell infiltration. Cancer vaccines can potentially be utilized as part of these combination immunotherapies to enhance antitumor efficacy through the expansion of tumor-reactive T cells. Utilizing murine models of colon and mammary carcinoma, here we investigated the effect of adding a recombinant adenovirus-based vaccine targeting tumor-associated antigens with an IL-15 super agonist adjuvant to a multimodal regimen consisting of a bifunctional anti-PD-L1/TGF-βRII agent along with a CXCR1/2 inhibitor. We demonstrate that the addition of vaccine induced a greater tumor infiltration with T cells highly positive for markers of proliferation and cytotoxicity. In addition to this enhancement of cytotoxic T cells, combination therapy showed a restructured tumor microenvironment with reduced T<sub>regs</sub> and CD11b<sup>+</sup>Ly6G<sup>+</sup> myeloid cells. Tumor-infiltrating immune cells exhibited an upregulation of gene signatures characteristic of a Th1 response and presented with a more diverse T-cell receptor (TCR) repertoire. These results provide the rationale for the addition of vaccine-to-immune checkpoint blockade-based therapies being tested in the clinic. |
| first_indexed | 2024-03-09T00:31:13Z |
| format | Article |
| id | doaj.art-2970619c774248aa9994464bbc9b217f |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-09T00:31:13Z |
| publishDate | 2021-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-2970619c774248aa9994464bbc9b217f2023-12-11T18:28:40ZengMDPI AGCancers2072-66942021-02-0113596810.3390/cancers13050968Vaccine Increases the Diversity and Activation of Intratumoral T Cells in the Context of Combination ImmunotherapyLucas A. Horn0Kristen Fousek1Duane H. Hamilton2James W. Hodge3John A. Zebala4Dean Y. Maeda5Jeffrey Schlom6Claudia Palena7Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USALaboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USALaboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USALaboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USASyntrix Pharmaceuticals, Auburn, WA 98001, USASyntrix Pharmaceuticals, Auburn, WA 98001, USALaboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USALaboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USAResistance to immune checkpoint blockade therapy has spurred the development of novel combinations of drugs tailored to specific cancer types, including non-inflamed tumors with low T-cell infiltration. Cancer vaccines can potentially be utilized as part of these combination immunotherapies to enhance antitumor efficacy through the expansion of tumor-reactive T cells. Utilizing murine models of colon and mammary carcinoma, here we investigated the effect of adding a recombinant adenovirus-based vaccine targeting tumor-associated antigens with an IL-15 super agonist adjuvant to a multimodal regimen consisting of a bifunctional anti-PD-L1/TGF-βRII agent along with a CXCR1/2 inhibitor. We demonstrate that the addition of vaccine induced a greater tumor infiltration with T cells highly positive for markers of proliferation and cytotoxicity. In addition to this enhancement of cytotoxic T cells, combination therapy showed a restructured tumor microenvironment with reduced T<sub>regs</sub> and CD11b<sup>+</sup>Ly6G<sup>+</sup> myeloid cells. Tumor-infiltrating immune cells exhibited an upregulation of gene signatures characteristic of a Th1 response and presented with a more diverse T-cell receptor (TCR) repertoire. These results provide the rationale for the addition of vaccine-to-immune checkpoint blockade-based therapies being tested in the clinic.https://www.mdpi.com/2072-6694/13/5/968cancer vaccinecombination immunotherapyTCR diversity |
| spellingShingle | Lucas A. Horn Kristen Fousek Duane H. Hamilton James W. Hodge John A. Zebala Dean Y. Maeda Jeffrey Schlom Claudia Palena Vaccine Increases the Diversity and Activation of Intratumoral T Cells in the Context of Combination Immunotherapy Cancers cancer vaccine combination immunotherapy TCR diversity |
| title | Vaccine Increases the Diversity and Activation of Intratumoral T Cells in the Context of Combination Immunotherapy |
| title_full | Vaccine Increases the Diversity and Activation of Intratumoral T Cells in the Context of Combination Immunotherapy |
| title_fullStr | Vaccine Increases the Diversity and Activation of Intratumoral T Cells in the Context of Combination Immunotherapy |
| title_full_unstemmed | Vaccine Increases the Diversity and Activation of Intratumoral T Cells in the Context of Combination Immunotherapy |
| title_short | Vaccine Increases the Diversity and Activation of Intratumoral T Cells in the Context of Combination Immunotherapy |
| title_sort | vaccine increases the diversity and activation of intratumoral t cells in the context of combination immunotherapy |
| topic | cancer vaccine combination immunotherapy TCR diversity |
| url | https://www.mdpi.com/2072-6694/13/5/968 |
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