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

Koji Nagaoka¹  Kazuhiro Kakimi¹  Changbo Sun¹  Yukari Kobayashi¹  Jun Nakajima²  Hidewaki Nakagawa³ 

[1] Department of Immunotherapeutics, The University of Tokyo Hospital, Tokyo 113-8655, Japan;Department of Thoracic Surgery, The University of Tokyo Graduate School of Medicine, Tokyo 113-8655, Japan;Laboratory for Cancer Genomics, RIKEN Center for Integrative Medical Sciences Kanagawa Japan, Yokohama 230-0045, Japan;

关键词: neoantigen;    DC vaccine;    immunotherapy;    checkpoint;    combination therapy;    tumor microenvironment;   

DOI  :  10.3390/cancers13215508

来源: DOAJ

【 摘 要 】

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⁺ T cell responses. However, they failed to inhibit LLC1 growth when incorporated into a cancer vaccine. In contrast, DCs pulsed with LPs induced CD4⁺ and CD8⁺ 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.

【 授权许可】

Unknown