Effector cells derived from naive T cells used in tumor immunotherapy of mice bearing B16 melanoma.
BACKGROUND
Adoptive cell transfer (ACT) immunotherapy has been used clinically for years to treat malignancies. Improving the killing efficiency of effector cells, such as tumor-specific cytotoxic T lymphocytes (CTLs), is an important component for enhancing the clinical response of cancer immunotherapy. Hence, we explored a novel method for preparing cancer-specific CTLs using naive T lymphocytes.


METHODS
C57BL/6 mice bearing B16 melanoma tumors were pretreated with cyclophosphamide (CTX) by peritoneal injection. The immunosuppressive influence of CTX on tumor regression and the tumor microenvironment was assessed. Naive T cells and T cell pools were isolated via negative selection using immunomagnetic beads. The proliferative potential and cytokine production of different T cell subpopulations were evaluated in vitro. Tumor-specific CTLs derived from naive T cells (naive CD4+ T cells: naive CD8+ T cells = 2:1) and pooled T cells were generated in vitro, respectively. B16 melanoma-bearing C57BL/6 mice were pretreated with CTX, followed by ACT immunotherapy using dendritic cell-induced CTLs. The homing abilities of the effector cells and interleukin-2 (IL-2), interferon-γ, granzyme B, and perforin mRNA levels in tumor tissues were evaluated, and the change in tumor volume was measured.


RESULTS
Mice receiving CTX peritoneal pretreatment injections did not display tumor regression compared with control mice. However, a significant downregulation of splenic Tregs and tumor growth factor-β1 (TGF-β1) and interleukin-10 (IL-10) serum levels was observed (P < 0.05). Naive T cells showed a stronger proliferative capacity and elevated cytokine production than did pooled T cells (P < 0.05). In addition, effector cells generated from naive T cells displayed more potent antitumor activity in vivo than those derived from pooled T cells (P < 0.05).


CONCLUSIONS
Effector cells derived from the naive T cells possess a stronger proliferative potential, homing capacity, and enhanced cytokine production, which leads to a superior antitumor response.
Department of Surgery, Hebei Medical University, Shijiazhuang, Hebei 050017, China; Department of Surgical Oncology, Affiliated Hospital of Hebei University, Baoding, Hebei 071000, China.
Ming
M
Wen
Department of Pediatric Surgery, the Second Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, China.
Weili
W
Xu
Department of Medical Oncology, Affiliated Hospital of Hebei University, Baoding, Hebei 071000, China.
Lili
L
Ren
Teaching & Research Section, Hebei Medical University, Shijiazhuang, Hebei 050017; Department of Surgery, Department of Oncology & Immunotherapy, Hebei General Hospital, Shijiazhuang, Hebei 050051, China.
Fei
F
Gao
Department of Surgical Oncology, Affiliated Hospital of Hebei University, Baoding, Hebei 071000, China.
Naipeng
N
Cui
Department of Surgery, Hebei Medical University, Shijiazhuang, Hebei 050017, China.
Junye
J
Wen
Department of Surgery, the Second Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, China.
Xinjiang
X
Li
Department of Surgery, the Second Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, China.
Lin
L
Lin
Department of Surgical Oncology, Affiliated Hospital of Hebei University, Baoding, Hebei 071000, China.
Zhenfeng
Z
Ma
Department of Surgical Oncology, Affiliated Hospital of Hebei University, Baoding, Hebei 071000, China.
Baoping
B
Chen
Teaching & Research Section, Hebei Medical University, Shijiazhuang, Hebei 050017; Department of Surgery, Department of Oncology & Immunotherapy, Hebei General Hospital, Shijiazhuang, Hebei 050051, China. Email: jianhuicai2001@163.com.
Jianhui
J
Cai
D000818:Animals; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D005260:Female; D005434:Flow Cytometry; D016219:Immunotherapy, Adoptive / Q000379:methods*; D008546:Melanoma, Experimental / Q000628:therapy*; D008810:Mice, Inbred C57BL