CD122+CD8+ Treg suppress vaccine-induced antitumor immune responses in lymphodepleted mice.
Lymphodeleption prior to adoptive transfer of tumor-specific T cells greatly improves the clinical efficacy of adoptive T-cell therapy for patients with advanced melanoma, and increases the therapeutic efficacy of cancer vaccines in animal models. Lymphodepletion reduces competition between lymphocytes, and thus creates "space" for enhanced expansion and survival of tumor-specific T cells. Within the lymphodepleted host, Ag-specific T cells still need to compete with other lymphocytes that undergo lymphopenia-driven proliferation. Herein, we describe the relative capacity of naïve T cells, Treg, and NK cells to undergo lymphopenia-driven proliferation. We found that the major population that underwent lymphopenia-driven proliferation was the CD122+ memory-like T-cell population (CD122+CD8+ Treg), and these cells competed with Ag-driven proliferation of melanoma-specific T cells. Removal of CD122+CD8+ Treg resulted in a greater expansion of tumor-specific T cells and tumor infiltration of functional effector/memory T cells. Our results demonstrate the lymphopenia-driven proliferation of CD122+CD8+ Treg in reconstituted lymphodepleted mice limited the antitumor efficacy of DC vaccination in conjunction with adoptive transfer of tumor-specific T cells.
Wang
Li-Xin
LX
Laboratory of Cancer Immunobiology, Earle A. Chiles Research Institute, Providence Portland Medical Center, Portland, OR 97213, USA.
Li
Yuhuan
Y
Yang
Guojun
G
Pang
Pui-yi
PY
Haley
Dan
D
Walker
Edwin B
EB
Urba
Walter J
WJ
Hu
Hong-Ming
HM
D000818:Animals; D016827:CD8 Antigens / Q000032:analysis; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000637:transplantation*; D019496:Cancer Vaccines / Q000276:immunology*; D002455:Cell Division; D003713:Dendritic Cells / Q000276:immunology* / Q000637:transplantation; D007156:Immunologic Memory; D016219:Immunotherapy, Adoptive; D019409:Interleukin-15 / Q000172:deficiency; D053646:Interleukin-2 Receptor beta Subunit / Q000032:analysis; D015851:Interleukin-7 / Q000494:pharmacology / Q000627:therapeutic use; D007694:Killer Cells, Natural / Q000166:cytology / Q000276:immunology; D008213:Lymphocyte Activation; D008212:Lymphocyte Depletion; D008231:Lymphopenia / Q000276:immunology*; D008546:Melanoma, Experimental / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D051379:Mice; D018345:Mice, Knockout; D011828:Radiation Chimera; D013154:Spleen / Q000166:cytology; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology*
D016827:CD8 Antigens; D019496:Cancer Vaccines; C508022:Il2rb protein, mouse; D019409:Interleukin-15; D053646:Interleukin-2 Receptor beta Subunit; D015851:Interleukin-7