Bystander elimination of antigen loss variants in established tumors

Abstract

Cancers express antigens that are targets for specific cytotoxic T lymphocytes (CTLs)1,2. However, cancer cells are genetically unstable3. Consequently, sub-populations of cancer cells that no longer express the target antigen may escape destruction by CTLs and grow progressively1,4,5,6,7,8,9,10,11,12,13. We show that cytotoxic T cells indirectly eliminate these antigen loss variants (ALVs) in a model system when the parental cancer cells express sufficient antigen to be effectively cross-presented by the tumor stroma. When the parental tumor expressed lower levels of antigen, cytotoxic T cells eradicated the antigen-positive parental cancer cells, but the ALVs escaped, grew and killed the host. By contrast, when the parental tumor expressed higher levels of antigen, cytotoxic T cells eradicated not only the parental cancer cells but also the ALVs. This 'bystander' elimination of ALVs required stromal cells expressing major histocompatibility complex (MHC) molecules capable of presenting the antigen, and occurred in tumors showing evidence of stromal destruction. ALVs were apparently eliminated indirectly when tumor-specific CTLs killed stromal cells that were cross-presenting antigen produced by and released from antigen-positive cancer cells. These results highlight the general importance of targeting the tumor stroma to prevent the escape of variant cancer cells.

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Figure 1: ALVs escape a systemic CTL response when tumors express low local levels of antigen.
Figure 2: ALVs escape when stromal cells do not cross-present antigen.
Figure 3: Elimination of ALVs does not correlate with greater infiltration of cytotoxic effector T cells, but does correlate with an increase in nonviable stromal cells.
Figure 4: Cross-presentation leads to arrest of tumor growth, whereas direct presentation leads to escape of ALVs.

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Acknowledgements

We thank B. Jabri and B. Meresse for excellent discussions; P. Ohashi and H. Hengartner for the cancer cell lines; A. Ma and M. Mescher for the OT-1 mice; M. Reth for the MerCreMer expression vector; H. Auer for synthesis of the SIYRYYGL peptide; C. Cham, T. Phillips and G. Beck-Engesser for technical advice; and The University of Chicago Immunology Applications Core Facility for technical assistance with flow cytometry. This work was supported by National Institutes of Health grants RO1-CA22677, RO1-CA37516 and PO1-CA97296, University of Chicago Cancer Research Center grant CA-14599, and a preclinical grant from the Cancer Research Institute. M.T.S. is a recipient of training grant HD 07009.

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Correspondence to Michael T Spiotto.

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Spiotto, M., Rowley, D. & Schreiber, H. Bystander elimination of antigen loss variants in established tumors. Nat Med 10, 294–298 (2004). https://doi.org/10.1038/nm999

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