Depletion of radio-resistant regulatory T cells enhances antitumor immunity during recovery from lymphopenia.
Cytotoxic lymphodepletion therapies augment antitumor immune responses. The generation and therapeutic efficacy of antitumor effector T cells (T(E)s) are enhanced during recovery from lymphopenia. Although the effects of lymphodepletion on naive T cells (T(N)s) and T(E)s have been studied extensively, the influence of lymphodepletion on suppressor cells remains poorly understood. In this study, we demonstrate a significant increase of CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs) in sublethally irradiated lymphopenic mice. These radio-resistant Tregs inhibited the induction of T(E)s in tumor-draining lymph-nodes (TDLNs) during recovery from lymphopenia. The transfer of T(N)s into lymphopenic tumor-bearing mice resulted in some antitumor effects; however, Treg depletion after whole-body irradiation and reconstitution strongly inhibited tumor progression. Further analyses revealed that tumor-specific T cells were primed from the transferred T(N)s, whereas the Tregs originated from irradiated recipient cells. As in irradiated lymphopenic mice, a high percentage of Tregs was observed in cyclophosphamide-treated lymphopenic mice. The inhibition of Tregs in cyclophosphamide-treated mice significantly reduced tumor growth. These results indicate that the Tregs that survive cytotoxic therapies suppress antitumor immunity during recovery from lymphopenia and suggest that approaches to deplete radio and chemo-resistant Tregs can enhance cancer immunotherapies.
Department of Medicine (II), Niigata University Medical and Dental Hospital, Niigata City, Niigata, Japan.
Junko
J
Baba
Satoshi
S
Watanabe
Yu
Y
Saida
Tomohiro
T
Tanaka
Takao
T
Miyabayashi
Jun
J
Koshio
Kosuke
K
Ichikawa
Koichiro
K
Nozaki
Toshiyuki
T
Koya
Katsuya
K
Deguchi
Chunrui
C
Tan
Satoru
S
Miura
Hiroshi
H
Tanaka
Junta
J
Tanaka
Hiroshi
H
Kagamu
Hirohisa
H
Yoshizawa
Ko
K
Nakata
Ichiei
I
Narita
D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D049109:Cell Proliferation; D003131:Combined Modality Therapy; D003520:Cyclophosphamide / Q000627:therapeutic use; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000378:metabolism; D008212:Lymphocyte Depletion; D008231:Lymphopenia / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011833:Radiation Injuries, Experimental / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D014916:Whole-Body Irradiation
D018906:Antineoplastic Agents, Alkylating; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D003520:Cyclophosphamide