CD40 Accelerates the Antigen-Specific Stem-Like Memory CD8+ T Cells Formation and Human Papilloma Virus (HPV)-Positive Tumor Eradication

Abstract

Antigen-specific stem-like memory CD8 + T cells (Tscm) have a series of stem cell characteristics, including long-term survival, self-renewal, anti-apoptosis and persistent differentiation into cytotoxic T cells. The effective induction of tumor-specific CD8 + Tscm could persistently eradicate tumor in pro-tumor hostile microenvironment. This study was to investigate the role of CD40 in HPV16-specific CD8 + Tscm induction and its anti-tumor function. We found that CD40 activation accelerated vaccine-induced HPV16 E7-specific CD8 + Tscm formation. Comparing to other HPV-specific CD8 + T cells, CD8 + Tscm were found to be stronger and long-term anti-tumor function, in vivo and in vitro, even in the adoptive cellular transferring model. Furthermore, high frequencies of Tscm might prevent the HPV infection to move on to the development of cancer. And the CD40 effect on Tscm involved Wnt/β-catenin activation. Our study suggest that CD40 activation supports the generation of tumor-specific CD8 + Tscm, thus providing new insight into cancer immunotherapy.

T-cell exhaustion and stemness in antitumor immunity: Characteristics, mechanisms, and implications

“…However, the mechanism by which such CD4 + T SCM exert antitumor effects remains unclear ( 109 ). In cervical cancer caused by human papillomavirus (HPV) infection, HPV16-specific CD8 + T SCM can induce long-term antitumor immunity and significantly inhibit tumor growth ( 143 ). The powerful immune reconstitution potential of T SCM indicates that T SCM can be useful in cancer treatment.…”

“…The costimulatory molecules ICOS, 4-1BB, and other T cell costimulatory molecules CD27, OX40(CD134), TNFR2, CD40 and GITR in TNFRSF (143,(166)(167)(168)(169) and the transcription repressor BTB domain and CNC homolog 2 (BACH2) (170,171), as the key regulators of stem cell-like T-cell subsets, induce the generation of stem cell-like lineages. Furthermore, the duration and intensity of the antigenic peptide/MHC-TCR interaction can affect T SCM expansion and maintenance.…”

Stem-like T cells and niches: Implications in human health and disease

“…Since T SCM cells are responsible for long-lasting memory of immune effect, T SCM may be an ideal target for prediction and improvement of vaccine effectiveness. Combination use of HPV vaccine with CD40 and TLR3 agonist produces increased number of CD8 + T SCM cells, mediating better therapeutic and preventive effects ( 262 ).…”

Stem cell-like memory T cells: The generation and application

“…Precise control of the TCR signaling strength may enhance Tscm generation to improve antitumor efficacy 61 . The combinatorial use of HPV peptide vaccines with CD40 antibody and TLR3 agonists generates more CD8 Tscm and thus mediates better therapeutic and preventive effects 99 …”