Selective targeting of Toll-like receptors and OX40 inhibit regulatory T-cell function in follicular lymphoma.
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.
Department of Immunology, The University of Texas M.D. Anderson Cancer Center, Houston, TX; Center for Cancer Immunology Research, The University of Texas M.D. Anderson Cancer Center, Houston, TX.
Kui Shin
KS
Voo
Myriam
M
Foglietta
Elena
E
Percivalle
Fuliang
F
Chu
Durga
D
Nattamai
Megan
M
Harline
Seung-Tae
ST
Lee
Laura
L
Bover
Heather Y
HY
Lin
Veerabhadran
V
Baladandayuthapani
David
D
Delgado
Amber
A
Luong
R Eric
RE
Davis
Larry W
LW
Kwak
Yong-Jun
YJ
Liu
Sattva S
SS
Neelapu
D000328:Adult; D000368:Aged; D018951:Antigens, CD20 / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D002469:Cell Separation; D003520:Cyclophosphamide / Q000494:pharmacology; D018572:Disease-Free Survival; D004317:Doxorubicin / Q000494:pharmacology; D005260:Female; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007167:Immunotherapy / Q000379:methods; D016753:Interleukin-10 / Q000378:metabolism; D008024:Ligands; D008224:Lymphoma, Follicular / Q000188:drug therapy* / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism; D053262:Receptors, OX40 / Q000378:metabolism*; D012074:Remission Induction; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000187:drug effects*; D051193:Toll-Like Receptors / Q000378:metabolism*; D016896:Treatment Outcome; D055815:Young Adult
D018951:Antigens, CD20; D000970:Antineoplastic Agents; C508609:IL10 protein, human; D007166:Immunosuppressive Agents; D008024:Ligands; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D053262:Receptors, OX40; C505716:TNFRSF4 protein, human; D051193:Toll-Like Receptors; D016753:Interleukin-10; D004317:Doxorubicin; D003520:Cyclophosphamide
OX40; Toll-like receptors; immunotherapy; lymphoma; regulatory T cells