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)
Kou Hioki, Marlous Wildemans, Youkyung Lim et al.· Journal of Immunology· 0 citations
Summary Background Despite effective suppression of HIV-1 replication by antiretroviral therapy (ART), persistent viral reservoirs prevent cure and necessitate lifelong treatment. While short-term dynamics of HIV-1 rebound following treatment interruption have been extensively studied, the longer-term consequences of immune perturbation and transient viraemia for reservoir quality and immune architecture remain incompletely understood. Methods We leveraged a rare historical human cohort that experienced prolonged viral rebound during a dendritic cell-based therapeutic vaccine study as a “perturbation model” to explore HIV-1 reservoir characteristics and immune remodelling more than a decade after ART resumption. We combined functional inducible HIV-1 reservoir measurements with high-dimensional immune phenotyping and included comparator analyses using a separate cohort of eight individuals with sustained ART-mediated suppression. Findings We observed higher inducible HIV-1 reservoir activity in nine participants from the Dendritic Cell-Tat, Rev, and Nef (DC-TRN) trial who previously experienced viral rebound and subsequently achieved viral re-suppression on long-term ART (p = 0.01). This increase in inducible HIV-1 reservoir activity occurred in the absence of major changes in total or intact proviral DNA (p = 0.99, and p = 0.35, respectively). Immune profiling suggested persistent differences in memory T cell phenotypes, after long-term re-suppression on ART, including enrichment of CXCR3-expressing central memory CD4+ T cells that positively correlated with inducible tat/rev msRNA expression (r2 = 0.54, p = 0.03). Interpretation Together, these findings suggest that immune perturbation and viral rebound may be associated with persistent changes in HIV-1 reservoir inducibility and immune architecture after viral re-suppression. Our study highlights a possible increase in inducible HIV-1 reservoir activity associated with a CXCR3+ memory T cell phenotype, supporting further evaluation of reservoir quality endpoints, candidate immunophenotypic correlates, and long-term monitoring strategies in contemporary remission trials. Funding This research was supported by grants from Aidsfonds (P-60602, P-263, P-53302, P-53601, P-60804), MRACE (EMC2020-083); Horizon Europe (681032); Health Holland (LSHM19100-SGF and EMCLSH19023), and NWO (ZonMW-40-44600-98-333).
C. Lungu, T. Hossain, Raquel Crespo et al.· EBioMedicine· 0 citations
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