Tim-3+ T-bet+ tumor-specific Th1 cells colocalize with and inhibit development and growth of murine neoplasms.
Although T cells infiltrate many types of murine and human neoplasms, in many instances tumor-specific cytotoxicity is not observed. Strategies to stimulate CTL-mediated antitumor immunity have included in vitro stimulation and/or genetic engineering of T cells, followed by adoptive transfer into tumor-bearing hosts. In this model of B cell lymphoma in SJL/J mice, we used Tim-3(+) T-bet(+) Th1 cells to facilitate the development of tumor-specific CTL. Tumor-specific Th1 cell lines were polarized with IL-12 during in vitro stimulation and long term maintenance. As few as 5 million Tim-3(+) T-bet(+) Th1 cells enabled recipients to resist growth of malignant transplantable cells. In addition, similar numbers of Th1 cells injected into 2- to 3-mo-old mice inhibited development of the spontaneous primary lymphomas, which normally arise in 90% of aging mice. CFSE(+) Th1 cells colocalized with injected tumor cells in vivo and formed conjugates with the tumor cells within follicles, whereas in nontumor-challenged recipients the CFSE(+) Th1 cells localized only within the T cell zones of the spleen. These results provide evidence that adoptive immunotherapy with Tim-3(+) T-bet(+) tumor-specific Th1 cells can be used to induce host cytotoxic responses that inhibit the development and growth of neoplastic cells.
Simmons
William J
WJ
Department of Pathology and Laboratory Medicine, University of Medicine and Dentistry of New Jersey-New Jersey Medical School and Graduate School Biomedical Sciences, Newark, NJ 07101, USA.
Koneru
Mythili
M
Mohindru
Mani
M
Thomas
Rajan
R
Cutro
Scott
S
Singh
Parul
P
Dekruyff
Rosemarie H
RH
Inghirami
Giorgio
G
Coyle
Anthony J
AJ
Kim
Byung S
BS
Ponzio
Nicholas M
NM
D019264:Adoptive Transfer; D000818:Animals; D002454:Cell Differentiation / Q000276:immunology*; D002455:Cell Division / Q000276:immunology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018920:Coculture Techniques; D004268:DNA-Binding Proteins / Q000502:physiology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D000072597:Hepatitis A Virus Cellular Receptor 2; D018664:Interleukin-12 / Q000502:physiology; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000473:pathology; D016393:Lymphoma, B-Cell / Q000276:immunology / Q000473:pathology* / Q000517:prevention & control*; D051379:Mice; D050778:NFATC Transcription Factors; D009368:Neoplasm Transplantation; D009687:Nuclear Proteins / Q000502:physiology; D011991:Receptors, Virus / Q000096:biosynthesis*; D020825:T-Box Domain Proteins; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000473:pathology; D018417:Th1 Cells / Q000276:immunology* / Q000473:pathology* / Q000637:transplantation; D014157:Transcription Factors / Q000096:biosynthesis* / Q000502:physiology; D000098815:T-bet Transcription Factor
D004268:DNA-Binding Proteins; D018984:Epitopes, T-Lymphocyte; C442241:Havcr2 protein, mouse; D000072597:Hepatitis A Virus Cellular Receptor 2; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D011991:Receptors, Virus; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D014157:Transcription Factors; D018664:Interleukin-12