Reciprocal changes in tumor antigenicity and antigen-specific T cell function during tumor progression.
Two seemingly incompatible models exist to explain the progression of cancers in immunocompetent hosts. The cancer immunosurveillance hypothesis posits that recognition of transformed cells by the immune system results in the generation of an effector response that may impede tumor growth. Clinically detectable cancer results from the emergence of tumor variants that escape this selective pressure. Alternatively, induction of immune tolerance to tumor antigens may enable cancer progression. We established a model where changes in the function of tumor-specific T cells and in tumor antigen expression could be followed during cancer progression. Early recognition of antigen led to activation, expansion, and effector function in tumor-specific CD4+ T cells resulting in the outgrowth of tumors expressing substantially reduced levels of antigen. Antigen loss was not complete, however, and levels remained above the threshold required for tumor-specific T cell recognition in vivo. In the face of persisting antigen, T cell tolerance ensued, leading to an impaired ability to mediate further antigen loss. Together, these studies establish that the processes of immunosurveillance and tumor editing coexist with a process in which the functional tumor-specific T cell repertoire is also "edited," reconciling two hypotheses historically central to our attempts to understand host antitumor immunity.
Zhou
Gang
G
Dept. of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, 1650 Orleans St., Ste. 4M51, Baltimore, MD 21231, USA.
Lu
Zhengbin
Z
McCadden
John D
JD
Levitsky
Hyam I
HI
Marson
Aimee L
AL
D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002277:Carcinoma / Q000276:immunology* / Q000473:pathology; D004195:Disease Models, Animal; D007108:Immune Tolerance / Q000276:immunology; D007680:Kidney Neoplasms / Q000276:immunology* / Q000473:pathology; D008213:Lymphocyte Activation / Q000276:immunology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D019139:Tumor Escape
D000951:Antigens, Neoplasm