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

Abstract

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.

FOXM1 Inhibition Enhances the Therapeutic Outcome of Lung Cancer Immunotherapy by Modulating PD‐L1 Expression and Cell Proliferation

“…It is reported that LLC‐1 tumors are resistant to ICI treatment. [ 25 ] Lewis lung carcinoma LLC‐1 murine lung cancer cells (5 × 10 5 ) were injected subcutaneously into C57BL/6N mice ( n = 6 per group) and allowed to form tumors with a volume of 150 mm 3 for 10 days. The mice were injected with TST at a dose of 17 mg kg −1 and anti‐4‐1BB antibody at a dose of 10 mg kg −1 at indicated time points represented by black arrows.…”

The role of innate immune cells in the tumor microenvironment and research progress in anti-tumor therapy

“…For example, DCVax-L, a DC vaccine against glioblastoma, which has been tested in phase III clinical trials and has shown prolonged overall survival in patients ( 79 ). In addition, another example is that a neoantigen dendritic cell vaccine combined with anti-CD38 and CpG can produce anti-tumor immunity against immune checkpoint therapy resistant mouse lung cancer cell lines, which further develops DC vaccine therapy ( 80 ). DC vaccine is a promising immunotherapy method, and relevant clinical trials are ongoing ( Table 1 ).…”

Research progress of neoantigen-based dendritic cell vaccines in pancreatic cancer

“…This candidate neoantigen short peptide L82 can both trigger CD8 + T-cell responses and suppress the LLC1 growth in vivo . THE L82-pulsed DC vaccination in combination with anti-CD38 antibody treatment effectively inhibited the tumor growth by reducing the tumor- infiltrated regulatory T cells ( 66 ). Furthermore, the effect of the combination of DC-loaded with MART-1 peptide vaccine with tremelimumab and the anti-CTLA-4 antibody was tested in melanoma, and the treatment strategy achieved a stronger and durable tumor response than each treatment alone ( 67 ).…”