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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Autores principales:	Changbo Sun, Koji Nagaoka, Yukari Kobayashi, Hidewaki Nakagawa, Kazuhiro Kakimi, Jun Nakajima
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	neoantigen DC vaccine immunotherapy checkpoint combination therapy tumor microenvironment Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/afe1b4a058b840f4ba974715b3c8fd04
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spelling	oai:doaj.org-article:afe1b4a058b840f4ba974715b3c8fd042021-11-11T15:33:48ZNeoantigen Dendritic Cell Vaccination Combined with Anti-CD38 and CpG Elicits Anti-Tumor Immunity against the Immune Checkpoint Therapy-Resistant Murine Lung Cancer Cell Line LLC110.3390/cancers132155082072-6694https://doaj.org/article/afe1b4a058b840f4ba974715b3c8fd042021-11-01T00:00:00Zhttps://www.mdpi.com/2072-6694/13/21/5508https://doaj.org/toc/2072-6694An 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.Changbo SunKoji NagaokaYukari KobayashiHidewaki NakagawaKazuhiro KakimiJun NakajimaMDPI AGarticleneoantigenDC vaccineimmunotherapycheckpointcombination therapytumor microenvironmentNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENCancers, Vol 13, Iss 5508, p 5508 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	neoantigen DC vaccine immunotherapy checkpoint combination therapy tumor microenvironment Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	neoantigen DC vaccine immunotherapy checkpoint combination therapy tumor microenvironment Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 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
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.
format	article
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
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_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_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_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
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/afe1b4a058b840f4ba974715b3c8fd04
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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

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