Therapeutic Efficacy of Cancer Stem Cell Vaccines in the Adjuvant Setting.
Dendritic cell (DC)-based vaccine strategies aimed at targeting cancer stem-like cells (CSC) may be most efficacious if deployed in the adjuvant setting. In this study, we offer preclinical evidence that this is the case for a CSC-DC vaccine as tested in murine models of SCC7 squamous cell cancer and D5 melanoma. Vaccination of mice with an ALDH(high) SCC7 CSC-DC vaccine after surgical excision of established SCC7 tumors reduced local tumor relapse and prolonged host survival. This effect was augmented significantly by simultaneous administration of anti-PD-L1, an immune checkpoint inhibitor. In the minimal disease setting of D5 melanoma, treatment of mice with ALDH(high) CSC-DC vaccination inhibited primary tumor growth, reduced spontaneous lung metastases, and increased host survival. In this setting, CCR10 and its ligands were downregulated on ALDH(high) D5 CSCs and in lung tissues, respectively, after vaccination with ALDH(high) D5 CSC-DC. RNAi-mediated attenuation of CCR10 blocked tumor cell migration in vitro and metastasis in vivo T cells harvested from mice vaccinated with ALDH(high) D5 CSC-DC selectively killed ALDH(high) D5 CSCs, with additional evidence of humoral immunologic engagement and a reduction in ALDH(high) cells in residual tumors. Overall, our results offered a preclinical proof of concept for the use of ALDH(high) CSC-DC vaccines in the adjuvant setting to more effectively limit local tumor recurrence and spontaneous pulmonary metastasis, as compared with traditional DC vaccines, with increased host survival further accentuated by simultaneous PD-L1 blockade. Cancer Res; 76(16); 4661-72. ©2016 AACR.
University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan. Center for Stem Cell Research and Application, Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Yangyang
Y
Hu
University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan. State Key Laboratory of Oncology in Southern China and Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou, China.
Lin
L
Lu
University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan. The Third Affiliated Hospital of Anhui Medical University, Hefei, China.
Yang
Y
Xia
University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan. Department of Oncology, Wuhan University, Renmin Hospital, Wuhan, China.
Xin
X
Chen
University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan.
Alfred E
AE
Chang
MedImmune Inc. Gaithersburg, Maryland.
Robert E
RE
Hollingsworth
MedImmune Inc. Gaithersburg, Maryland.
Elaine
E
Hurt
University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan.
John
J
Owen
University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan.
Jeffrey S
JS
Moyer
University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan.
Mark E P
ME
Prince
The Third Affiliated Hospital of Anhui Medical University, Hefei, China.
Fu
F
Dai
The Third Affiliated Hospital of Anhui Medical University, Hefei, China.
Yangyi
Y
Bao
The Third Affiliated Hospital of Anhui Medical University, Hefei, China.
Yi
Y
Wang
University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan.
Joel
J
Whitfield
State Key Laboratory of Oncology in Southern China and Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou, China.
Jian-Chuan
JC
Xia
Center for Stem Cell Research and Application, Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. qiaoli@umich.edu mwicha@umich.edu sa2huang@hotmail.com.
Shiang
S
Huang
University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan. qiaoli@umich.edu mwicha@umich.edu sa2huang@hotmail.com.
Max S
MS
Wicha
University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan. qiaoli@umich.edu mwicha@umich.edu sa2huang@hotmail.com.
Qiao
Q
Li
D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000444:Aldehyde Dehydrogenase / Q000378:metabolism; D000818:Animals; D019496:Cancer Vaccines / Q000276:immunology / Q000494:pharmacology*; D003713:Dendritic Cells / Q000276:immunology*; D004195:Disease Models, Animal; D005260:Female; D005434:Flow Cytometry; D055785:Gene Knockdown Techniques; D008546:Melanoma, Experimental; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018307:Neoplasms, Squamous Cell; D014411:Neoplastic Stem Cells / Q000276:immunology*
D000276:Adjuvants, Immunologic; D019496:Cancer Vaccines; D000444:Aldehyde Dehydrogenase