Autoimmune B-cell lymphopenia after successful adoptive therapy with telomerase-specific T lymphocytes.
Telomerase reverse transcriptase (TERT) is a good candidate for cancer immunotherapy because it is overexpressed in 85% of all human tumors and implicated in maintenance of the transformed phenotype. TERT-based cancer vaccines have been shown to be safe, not inducing any immune-related pathology, but their impact on tumor progression is modest. Here we show that adoptive cell therapy with the use of high-avidity T lymphocytes reactive against telomerase can control the growth of different established tumors. Moreover, in transgenic adenocarcinoma mouse prostate mice, which develop prostate cancer, TERT-based adoptive cell therapy halted the progression to more aggressive and poorly differentiated tumors, significantly prolonging mouse survival. We also demonstrated that human tumors, including Burkitt lymphoma, and human cancer stem cells, are targeted in vivo by TERT-specific cytotoxic T lymphocytes. Effective therapy with T cells against telomerase, different from active vaccination, however, led to autoimmunity marked by a consistent, although transient, B-cell depletion in primary and secondary lymphoid organs, associated with alteration of the spleen cytoarchitecture. These results indicate B cells as an in vivo target of TERT-specific cytotoxic T lymphocytes during successful immunotherapy.
Ugel
Stefano
S
Department of Oncology and Surgical Sciences, Padova, Italy.
Scarselli
Elisa
E
Iezzi
Manuela
M
Mennuni
Carmela
C
Pannellini
Tania
T
Calvaruso
Francesco
F
Cipriani
Barbara
B
De Palma
Raffaele
R
Ricci-Vitiani
Lucia
L
Peranzoni
Elisa
E
Musiani
Piero
P
Zanovello
Paola
P
Bronte
Vincenzo
V
D000230:Adenocarcinoma / Q000276:immunology / Q000628:therapy*; D019264:Adoptive Transfer / Q000379:methods*; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000473:pathology; D001854:Bone Marrow Cells / Q000473:pathology; D019496:Cancer Vaccines; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms; D004195:Disease Models, Animal; D015789:HLA-A2 Antigen / Q000235:genetics / Q000276:immunology; D008175:Lung Neoplasms; D008231:Lymphopenia / Q000473:pathology*; D008297:Male; D008545:Melanoma; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009368:Neoplasm Transplantation; D011471:Prostatic Neoplasms / Q000276:immunology / Q000628:therapy*; D012878:Skin Neoplasms; D013154:Spleen / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology / Q000637:transplantation*; D019098:Telomerase / Q000276:immunology*
D019496:Cancer Vaccines; D015789:HLA-A2 Antigen; C509186:TERT protein, human; D019098:Telomerase; C509187:Tert protein, mouse