Prime-Target neoantigen vaccination strategy enhances neoantigen-specific T cell immunity at the tumor microenvironment in murine cold tumor models 2256928

Abstract

Despite their great promise in cancer treatment, the clinical efficacy of therapeutic cancer vaccines against solid tumors remains limited because of the immunosuppressive cold tumor microenvironment (TME), which suppresses anti-tumor T-cell activity. To overcome this, we propose a novel “Prime-Target” neoantigen vaccination strategy (referred to as P/T vaccination) that combines subcutaneous (SQ) and intra-tumor (IT) neopeptide vaccinations with a potent adjuvant combination of K3 CpG plus c-di-AMP (K3/c-di-AMP). This strategy first primes systemic neopeptide-specific T cell responses and then targets cold tumors by recruiting neopeptide-specific T cells into TME. Murine cold tumors that are resistant to immunotherapy such as mesothelioma (AE17) and pancreatic adenocarcinoma (KPC-4662) were vaccinated with SQ priming followed by IT boosting using corresponding neopeptides plus K3/c-di-AMP. Tumor growth and survival were assessed. Immune responses in the tumors were analyzed by flow cytometry and single-cell RNA/TCR sequencing. P/T vaccination markedly suppressed tumor growth and prolonged survival. These therapeutic effects require intratumoral delivery of the full neopeptide vaccine, as neither IT adjuvants nor neopeptides alone after SQ vaccination, confer protection. Mechanistically, P/T vaccination recruits massive novel TCR clones of neoantigen-specific CD4+ Th1 cells and effector CD8+ T cells into the tumor, while markedly increasing effector T cell/Treg ratios and reducing M2 macrophages within the TME. The Prime-Target neoantigen vaccination elicits potent systemic anti-tumor T cell immunity and directs it to the tumor. This dramatically alters the TME, remodeling it towards an effector phenotype that is more favorable for tumor control. This novel approach provides a mechanistic framework for optimizing neoantigen vaccination strategies against immunosuppressive cold solid tumors. the Department of Immunology of the Erasmus MC, the Dutch Cancer Society (KWF Grant 12837), International Joint Usage/Research Center, the Institute of Medical Science, the University of Tokyo (Project number K22-3063 and K25-3190) Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)