Depletion of endogenous tumor-associated regulatory T cells improves the efficacy of adoptive cytotoxic T-cell immunotherapy in murine acute myeloid leukemia.
Tumor-induced immune suppression can permit tumor cells to escape host immune resistance. To elucidate host factors contributing to the poor response of adoptively transferred tumor-reactive cytotoxic T lymphocytes (CTLs), we used a systemic model of murine acute myeloid leukemia (AML). AML progression resulted in a progressive regulatory T-cell (Treg) accumulation in disease sites. The adoptive transfer of in vitro-generated, potently lytic anti-AML-reactive CTLs failed to reduce disease burden or extend survival. Compared with non-AML-bearing hosts, transferred CTLs had reduced proliferation in AML sites of metastases. Treg depletion by a brief course of interleukin-2 diphtheria toxin (IL-2DT) transiently reduced AML disease burden but did not permit long-term survival. In contrast, IL-2DT prevented anti-AML CTL hypoproliferation, increased the number of transferred CTLs at AML disease sites, reduced AML tumor burden, and resulted in long-term survivors that sustained an anti-AML memory response. These data demonstrated that Tregs present at AML disease sites suppress adoptively transferred CTL proliferation, limiting their in vivo expansion, and Treg depletion before CTL transfer can result in therapeutic efficacy in settings of substantial pre-existing tumor burden in which antitumor reactive CTL infusion alone has proven ineffective.
Zhou
Qing
Q
Department of Pediatrics, Division of Blood and Marrow Transplantation, Masonic Cancer Center, University of Minnesota, Twin Cities, Minneapolis, MN 55455, USA.
Bucher
Christoph
C
Munger
Meghan E
ME
Highfill
Steven L
SL
Tolar
Jakub
J
Munn
David H
DH
Levine
Bruce L
BL
Riddle
Megan
M
June
Carl H
CH
Vallera
Daniel A
DA
Weigel
Brenda J
BJ
Blazar
Bruce R
BR
D019264:Adoptive Transfer; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D004167:Diphtheria Toxin / Q000494:pharmacology; D004195:Disease Models, Animal; D006801:Humans; D007156:Immunologic Memory / Q000187:drug effects; D007376:Interleukin-2 / Q000494:pharmacology; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D008212:Lymphocyte Depletion; D051379:Mice; D018345:Mice, Knockout; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000637:transplantation*; D050378:T-Lymphocytes, Regulatory; D019139:Tumor Escape / Q000187:drug effects / Q000276:immunology
D004167:Diphtheria Toxin; D007376:Interleukin-2; D011993:Recombinant Fusion Proteins; C062518:interleukin 2-diphtheria toxin