Neoantigen Dendritic Cell Vaccination Combined with Anti-CD38 and CpG Elicits Anti-Tumor Immunity against the Immune Checkpoint Therapy-Resistant Murine Lung Cancer Cell Line LLC1
An important factor associated with primary resistance to immune-checkpoint therapies (ICT) is a “cold” tumor microenvironment (TME), characterized by the absence of T cell infiltration and a non-inflammatory milieu. Whole-exome and RNA sequencing to predict neoantigen expression was performed on th...
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| Format: | Article |
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MDPI AG
2021-11-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/13/21/5508 |
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| author | Changbo Sun Koji Nagaoka Yukari Kobayashi Hidewaki Nakagawa Kazuhiro Kakimi Jun Nakajima |
| author_facet | Changbo Sun Koji Nagaoka Yukari Kobayashi Hidewaki Nakagawa Kazuhiro Kakimi Jun Nakajima |
| author_sort | Changbo Sun |
| collection | DOAJ |
| description | An important factor associated with primary resistance to immune-checkpoint therapies (ICT) is a “cold” tumor microenvironment (TME), characterized by the absence of T cell infiltration and a non-inflammatory milieu. Whole-exome and RNA sequencing to predict neoantigen expression was performed on the LLC1 cell line which forms “cold” tumors in mice. Dendritic cell (DC)-based vaccination strategies were developed using candidate neoantigen long peptides (LPs). A total of 2536 missense mutations were identified in LLC1 and of 132 candidate neoantigen short peptides, 25 were found to induce CD8<sup>+</sup> T cell responses. However, they failed to inhibit LLC1 growth when incorporated into a cancer vaccine. In contrast, DCs pulsed with LPs induced CD4<sup>+</sup> and CD8<sup>+</sup> T cell responses and one of them, designated L82, delayed LLC1 growth in vivo. By RNA-Seq, CD38 was highly expressed by LLC1 tumor cells and, therefore, anti-CD38 antibody treatment was combined with L82-pulsed DC vaccination. This combination effectively suppressed tumor growth via a mechanism relying on decreased regulatory T cells in the tumor. This study demonstrated that an appropriate vaccination strategy combining neoantigen peptide-pulsed DC with anti-CD38 antibody can render an ICT-resistant “cold” tumor susceptible to immune rejection via a mechanism involving neutralization of regulatory T cells. |
| first_indexed | 2024-03-10T06:04:52Z |
| format | Article |
| id | doaj.art-afe1b4a058b840f4ba974715b3c8fd04 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T06:04:52Z |
| publishDate | 2021-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-afe1b4a058b840f4ba974715b3c8fd042023-11-22T20:36:20ZengMDPI AGCancers2072-66942021-11-011321550810.3390/cancers13215508Neoantigen Dendritic Cell Vaccination Combined with Anti-CD38 and CpG Elicits Anti-Tumor Immunity against the Immune Checkpoint Therapy-Resistant Murine Lung Cancer Cell Line LLC1Changbo Sun0Koji Nagaoka1Yukari Kobayashi2Hidewaki Nakagawa3Kazuhiro Kakimi4Jun Nakajima5Department of Immunotherapeutics, The University of Tokyo Hospital, Tokyo 113-8655, JapanDepartment of Immunotherapeutics, The University of Tokyo Hospital, Tokyo 113-8655, JapanDepartment of Immunotherapeutics, The University of Tokyo Hospital, Tokyo 113-8655, JapanLaboratory for Cancer Genomics, RIKEN Center for Integrative Medical Sciences Kanagawa Japan, Yokohama 230-0045, JapanDepartment of Immunotherapeutics, The University of Tokyo Hospital, Tokyo 113-8655, JapanDepartment of Thoracic Surgery, The University of Tokyo Graduate School of Medicine, Tokyo 113-8655, JapanAn important factor associated with primary resistance to immune-checkpoint therapies (ICT) is a “cold” tumor microenvironment (TME), characterized by the absence of T cell infiltration and a non-inflammatory milieu. Whole-exome and RNA sequencing to predict neoantigen expression was performed on the LLC1 cell line which forms “cold” tumors in mice. Dendritic cell (DC)-based vaccination strategies were developed using candidate neoantigen long peptides (LPs). A total of 2536 missense mutations were identified in LLC1 and of 132 candidate neoantigen short peptides, 25 were found to induce CD8<sup>+</sup> T cell responses. However, they failed to inhibit LLC1 growth when incorporated into a cancer vaccine. In contrast, DCs pulsed with LPs induced CD4<sup>+</sup> and CD8<sup>+</sup> T cell responses and one of them, designated L82, delayed LLC1 growth in vivo. By RNA-Seq, CD38 was highly expressed by LLC1 tumor cells and, therefore, anti-CD38 antibody treatment was combined with L82-pulsed DC vaccination. This combination effectively suppressed tumor growth via a mechanism relying on decreased regulatory T cells in the tumor. This study demonstrated that an appropriate vaccination strategy combining neoantigen peptide-pulsed DC with anti-CD38 antibody can render an ICT-resistant “cold” tumor susceptible to immune rejection via a mechanism involving neutralization of regulatory T cells.https://www.mdpi.com/2072-6694/13/21/5508neoantigenDC vaccineimmunotherapycheckpointcombination therapytumor microenvironment |
| spellingShingle | Changbo Sun Koji Nagaoka Yukari Kobayashi Hidewaki Nakagawa Kazuhiro Kakimi Jun Nakajima Neoantigen Dendritic Cell Vaccination Combined with Anti-CD38 and CpG Elicits Anti-Tumor Immunity against the Immune Checkpoint Therapy-Resistant Murine Lung Cancer Cell Line LLC1 Cancers neoantigen DC vaccine immunotherapy checkpoint combination therapy tumor microenvironment |
| title | Neoantigen Dendritic Cell Vaccination Combined with Anti-CD38 and CpG Elicits Anti-Tumor Immunity against the Immune Checkpoint Therapy-Resistant Murine Lung Cancer Cell Line LLC1 |
| title_full | Neoantigen Dendritic Cell Vaccination Combined with Anti-CD38 and CpG Elicits Anti-Tumor Immunity against the Immune Checkpoint Therapy-Resistant Murine Lung Cancer Cell Line LLC1 |
| title_fullStr | Neoantigen Dendritic Cell Vaccination Combined with Anti-CD38 and CpG Elicits Anti-Tumor Immunity against the Immune Checkpoint Therapy-Resistant Murine Lung Cancer Cell Line LLC1 |
| title_full_unstemmed | Neoantigen Dendritic Cell Vaccination Combined with Anti-CD38 and CpG Elicits Anti-Tumor Immunity against the Immune Checkpoint Therapy-Resistant Murine Lung Cancer Cell Line LLC1 |
| title_short | Neoantigen Dendritic Cell Vaccination Combined with Anti-CD38 and CpG Elicits Anti-Tumor Immunity against the Immune Checkpoint Therapy-Resistant Murine Lung Cancer Cell Line LLC1 |
| title_sort | neoantigen dendritic cell vaccination combined with anti cd38 and cpg elicits anti tumor immunity against the immune checkpoint therapy resistant murine lung cancer cell line llc1 |
| topic | neoantigen DC vaccine immunotherapy checkpoint combination therapy tumor microenvironment |
| url | https://www.mdpi.com/2072-6694/13/21/5508 |
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