IFN-gamma mediates CD4+ T-cell loss and impairs secondary antitumor responses after successful initial immunotherapy.
Protective cell-mediated immune responses in cancer are critically dependent on T-helper type 1 (T(H)1) cytokines such as interferon-gamma (IFN-gamma). We have previously shown that the combination of CD40 stimulation and interleukin-2 (IL-2) leads to synergistic antitumor responses in several models of advanced metastatic disease. We now report that after this treatment and other immunotherapy regimens, the CD4+ T-cell population, in contrast to CD8+ T cells, did not significantly increase but rather exhibited a substantial level of apoptosis that was dependent on IFN-gamma. Mice immunized with tumor cells and treated with an immunotherapy regimen that was initially protective were later unable to mount effective memory responses compared with immunized mice not receiving immunotherapy. Immunotherapy given to tumor-bearing Ifngr-/- mice resulted in restoration of secondary responses. Thus, although immunotherapeutic regimens inducing strong IFN-gamma responses can lead to successful early antitumor efficacy, they may also impair the development of durable antitumor responses.
Berner
Vanessa
V
Department of Microbiology and Immunology, University of Nevada at Reno, Reno, Nevada 89557, USA.
Liu
Haiyan
H
Zhou
Qing
Q
Alderson
Kory L
KL
Sun
Kai
K
Weiss
Jonathan M
JM
Back
Timothy C
TC
Longo
Dan L
DL
Blazar
Bruce R
BR
Wiltrout
Robert H
RH
Welniak
Lisbeth A
LA
Redelman
Doug
D
Murphy
William J
WJ
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D002292:Carcinoma, Renal Cell / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D002460:Cell Line; D002478:Cells, Cultured; D017637:Clonal Deletion / Q000235:genetics / Q000276:immunology; D005260:Female; D007156:Immunologic Memory / Q000235:genetics; D016233:Immunotherapy, Active; D007371:Interferon-gamma / Q000502:physiology*; D007680:Kidney Neoplasms / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D008546:Melanoma, Experimental / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic
D007371:Interferon-gamma