T cell homeostatic proliferation elicits effective antitumor autoimmunity.
Development of tumor immunotherapies focuses on inducing autoimmune responses against tumor-associated self-antigens primarily encoded by normal, unmutated genes. We hypothesized that such responses could be elicited by T cell homeostatic proliferation in the periphery, involving expansion of T cells recognizing self-MHC/peptide ligands. Herein, we demonstrate that sublethally irradiated lymphopenic mice transfused with autologous or syngeneic T cells showed tumor growth inhibition when challenged with melanoma or colon carcinoma cells. Importantly, the antitumor response depended on homeostatic expansion of a polyclonal T cell population within lymph nodes. This response was effective even for established tumors, was characterized by CD8(+) T cell-mediated tumor-specific cytotoxicity and IFN-gamma production, and was associated with long-term memory. The results indicate that concomitant induction of the physiologic processes of homeostatic T cell proliferation and tumor antigen presentation in lymph nodes triggers a beneficial antitumor autoimmune response.
Department of Immunology, The Scripps Research Institute, La Jolla, California 92037, USA.
Wolfgang
W
Dummer
Andreas G
AG
Niethammer
Roberto
R
Baccala
Brian R
BR
Lawson
Norbert
N
Wagner
Ralph A
RA
Reisfeld
Argyrios N
AN
Theofilopoulos
D000818:Animals; D017951:Antigen Presentation; D000951:Antigens, Neoplasm; D001324:Autoantigens; D015551:Autoimmunity; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D003110:Colonic Neoplasms / Q000276:immunology / Q000628:therapy; D003602:Cytotoxicity, Immunologic; D006706:Homeostasis; D007156:Immunologic Memory; D007167:Immunotherapy; D007371:Interferon-gamma / Q000096:biosynthesis; D008213:Lymphocyte Activation; D008546:Melanoma, Experimental / Q000276:immunology / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009374:Neoplasms, Experimental / Q000276:immunology* / Q000628:therapy*; D013601:T-Lymphocytes / Q000276:immunology* / Q000637:transplantation; D014820:Vitiligo / Q000276:immunology / Q000473:pathology
D000951:Antigens, Neoplasm; D001324:Autoantigens; D007371:Interferon-gamma