IFN-γ– and TNF-dependent bystander eradication of antigen-loss variants in established mouse cancers
Bin Zhang, … , Donald A. Rowley, Hans Schreiber
Bin Zhang, … , Donald A. Rowley, Hans Schreiber
Published March 3, 2008
Citation Information: J Clin Invest. 2008;118(4):1398-1404. https://doi.org/10.1172/JCI33522.
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Research Article Oncology

IFN-γ– and TNF-dependent bystander eradication of antigen-loss variants in established mouse cancers

Abstract

Tumors elicit antitumor immune responses, but over time they evolve and can escape immune control through various mechanisms, including the loss of the antigen to which the response is directed. The escape of antigen-loss variants (ALVs) is a major obstacle to T cell–based immunotherapy for cancer. However, cancers can be cured if both the number of CTLs and the expression of antigen are high enough to allow targeting of not only tumor cells, but also the tumor stroma. Here, we showed that IFN-γ and TNF produced by CTLs were crucial for the elimination of established mouse tumors, including ALVs. In addition, both BM- and non-BM–derived stromal cells were required to express TNF receptors and IFN-γ receptors for the elimination of ALVs. Although IFN-γ and TNF were not required by CTLs for perforin-mediated killing of antigen-expressing tumor cells, the strong inference is that tumor antigen–specific CTLs must secrete IFN-γ and TNF for destruction of tumor stroma. Therefore, bystander killing of ALVs may result from IFN-γ and TNF acting on tumor stroma.

Authors

Bin Zhang, Theodore Karrison, Donald A. Rowley, Hans Schreiber

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Figure 1

IFN-γ and TNF produced by T cells are needed for rejection of established tumors.

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IFN-γ and TNF produced by T cells are needed for rejection of establishe...
OT-1 transgenic mice were injected s.c. with 2 × 106 MC57-SIY-Hi cells; on day 14, the SIY-immune T cells from WT and Prf–/– mice, as well as no T cells as controls (left), and the SIY-immune T cells from WT, TNF–/–, and IFN-γ–/– mice (middle) were adoptively transferred into the tumor-bearing mice. Results were pooled from 3 experiments, each controlled by tumor-bearing mice treated with WT T cells. Right: OT-1 transgenic mice were injected s.c. with 2 × 106 MC57-SIY-Hi cells plus 2 × 103 MC57 cells. At day 14, the SIY-immune T cells from WT, TNF–/–, and IFN-γ–/– mice were adoptively transferred into the tumor-bearing mice. The generation of SIY-immune T cells is described in Methods. Each curve represents an individual mouse.