Augmentation of anti-tumor responses of adoptively transferred CD8+T cells in the lymphopenic setting by HSV amplicon transduction.
Treatment of cancer with cytotoxic agents may induce lymphopenia. Adoptively transferred T cells have been reported to display enhanced anti-tumor efficacy in the lymphopenic setting. We reasoned that the anti-tumor effects of adoptively transferred cells in the lymphopenic host could be further augmented through local provision of an innate stimulus in the tumor bed. Utilizing a model in which mice were irradiated to induce lymphopenia, with limited shielding to allow tumor growth, we demonstrate that "triple" therapy consisting of radiation-induced lymphopenia, adoptive transfer of naïve CD8+ T cells, and intra-tumoral HSV amplicon injection resulted in reduced tumor growth compared to the combination of any two of the aforementioned interventions. To gain insight into the mechanism underlying this effect we studied the effects of HSV amplicon transduction into tumors on cytokine expression and on anti-tumor specific T cells. HSV amplicon transduction specifically induced several cytokine mRNAs including IFN-gamma, and IP-10. Adoptively transferred transgenic OT-1 T cells directed against Ovalbumin were more effective against Ovalbumin-expressing tumors when combined with intra-tumoral HSV amplicon injections in the lymphopenic host. Following intra-tumoral HSV-amplicon injections, anti-tumor T cells secreted higher levels of interferon-gamma in response to in-vitro re-stimulation with tumor cells, implying that HSV amplicon injection provided a strong signal for T cell activation. Combining adoptive transfer of naïve T cells in the lymphopenic setting with local T cell stimulation may facilitate expansion and activation of anti-tumor T cell populations in vivo, resulting in enhanced anti-tumor responses without the need to resort to prolonged in vitro T cell culture and/or manipulation.
Nechushtan
Hovav
H
Department of Medicine, Miller School of Medicine at the University of Miami, Sylvester Comprehensive Cancer Center, Miami, FL 33136, USA.
Pham
Dien
D
Zhang
Yu
Y
Morgensztern
Daniel
D
Yi
Kyung H
KH
Shin
Seung-Uon
SU
Federoff
Howard J
HJ
Bowers
William J
WJ
Tolba
Khaled A
KA
Rosenblatt
Joseph D
JD
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000637:transplantation*; D002460:Cell Line; D016207:Cytokines / Q000235:genetics / Q000276:immunology; D005434:Flow Cytometry; D005814:Genes, Viral; D016219:Immunotherapy, Adoptive / Q000379:methods*; D008213:Lymphocyte Activation / Q000276:immunology; D008231:Lymphopenia; D051379:Mice; D009374:Neoplasms, Experimental / Q000276:immunology / Q000628:therapy*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018139:Simplexvirus / Q000235:genetics* / Q000276:immunology; D014161:Transduction, Genetic
D016207:Cytokines