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Selective targeting of Toll-like receptors and OX40 inhibit regulatory T cell function in follicular lymphoma
- Publication Year :
- 2014
-
Abstract
- Immunotherapeutic strategies are promising approaches for the treatment of follicular lymphoma (FL). However, their efficacy may be limited by immunosuppressive elements in the immune system and tumor microenvironment. Therefore, strategies to reverse the effects of the immunosuppressive elements are needed. We observed that regulatory T cells (Tregs) were increased in the peripheral blood at diagnosis and persisted in high numbers after induction of clinical remission with a cyclophosphamide and doxorubicin-containing chemotherapy regimen in FL patients. High levels of peripheral blood Tregs prior to therapy were associated with decreased progression-free survival in FL patients treated with either chemotherapy or combination immunotherapy that targeted CD20 and PD-1 with monoclonal antibodies rituximab and pidilizumab, respectively. Intratumoral and peripheral blood Tregs potently suppressed autologous antitumor effector T cells in FL. However, the effects of FL Tregs could be reversed by triggering Toll-like receptors (TLR) with TLR ligands Pam3 CSK4 (TLR 1/2), flagellin (TLR 5), and CpG-B (TLR 9), and/or OX40. The TLR ligands synergized with each other as well as OX40 signaling to inhibit Tregs. Furthermore, they restored the function of FL tumor-specific effector T cells. Our results suggest that a state of tolerance exists in FL patients at diagnosis and after induction of clinical remission, and agents that activate TLRs 1/2, 5, and 9, and OX40 may serve as adjuvants to enhance the efficacy of antitumor immunotherapeutic strategies and preventive vaccines against infectious diseases in these patients.
- Subjects :
- Adult
Male
Programmed Cell Death 1 Receptor
Antineoplastic Agents
Cell Separation
Ligands
T-Lymphocytes, Regulatory
Article
Disease-Free Survival
Young Adult
Cell Line, Tumor
Humans
Cyclophosphamide
Lymphoma, Follicular
Aged
Remission Induction
Toll-Like Receptors
Middle Aged
Receptors, OX40
Antigens, CD20
Flow Cytometry
Interleukin-10
Gene Expression Regulation, Neoplastic
Treatment Outcome
Doxorubicin
Female
Immunotherapy
Immunosuppressive Agents
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.pmid..........a348dec2ced3b01c61fca670e708e6c9