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 3

TNF and IFN-γ are not required for SIY-specific T cell killing in vivo.

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TNF and IFN-γ are not required for SIY-specific T cell killing in vivo. ...
(A) Flow cytometric data showing representative examples of results. Left: SIY-pulsed (CFSE-high) or gp33-pulsed (CFSE-low) target cells from C57BL/6 WT, IFN-γR–/–, TNFR–/–, or lpr mice were transferred into C57BL/6 WT mice. Right: SIY-pulsed or gp33-pulsed target cells from C57BL/6 WT mice were transferred into IFN-γ–/–, TNF–/–, or Prf–/– mice. Recipient mice were immunized with MC57-SIY-Hi cells 8 d prior to injection of target cells to generate host effector T cells. The unimmunized WT mice receiving target cells were used as controls (bottom right). Spleens were harvested 24 h later and analyzed for CFSE fluorescence. (B and C) Compiled data of percentage of killing. (B) n = 3 per group, pooled from 2 independent experiments. (C) n = 2 (WT and Ipr) or 4 (IFN-γR–/– and TNFR–/–), pooled from 2 independent experiments.