Volume 3 Supplement 2

30th Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2015)

Open Access

Immune surveillance is thwarted by tumor-cell intrinsic beta-catenin signaling

  • Stefani Spranger1,
  • Brendan Horton1 and
  • Thomas F Gajewski2
Journal for ImmunoTherapy of Cancer20153(Suppl 2):P418

DOI: 10.1186/2051-1426-3-S2-P418

Published: 4 November 2015

Growing evidence has emerged that subgroups of cancer patients have a spontaneous T cell-centered immune response reflected by infiltration of antigen-specific CD8+ T cells into the tumor microenvironment. However, another major subgroup of patients completely lacks T cell infiltration. Importantly, the presence of tumor-infiltrating CD8+ T cells has been correlated with clinical response to anti-PD-1 mAb and other immunotherapies. Recent work from our laboratory has revealed that activation of the Wnt/β-catenin pathway within tumor cells can mediate exclusion of T cells from the tumor microenvironment. Using an autochthonous inducible mouse model for melanoma (BrafV600E/PTEN-/-; BP) with or without stabilized β-catenin (BrafV600E/PTEN-/-/CAT-STA; BPC) we showed that T cell exclusion from the tumor microenvironment was due to failed recruitment of Batf3-lineage dendritic cells, resulting in a defective early T cell priming and absence of systemic immunity. However, whether tumor-intrinsic β-catenin signaling might mediate tumor resistance after an anti-tumor T cell response was established is not known. To test this notion, we used a spontaneously rejected cell line (MC57.SIY) to induce immunologic memory. These tumors were implanted into naïve BP and BPC mice that had been crossed to a Rosa26-LSL-SIY inducible antigen mouse and following complete regression of the primary (MC57.SIY) tumor, the genetically-induced melanomas were initiated. Although the primary SIY-specific CD8+ T cell response and the induced memory response were comparable between both tumor models, tumor protection was observed against BP-SIY tumors but not BPC-SIY tumors. Increased tumor control in BP-SIY mice was accompanied by strong T cell infiltration and a boosted memory response. These results indicate that tumor-intrinsic β-catenin signaling can mediate exclusion of effector T cell migration. To test this notion directly, we adoptively transferred in vitro-activated SIY-reactive T cell receptor transgenic T cells (2C T cells) into BP-SIY and BPC-SIY tumor-bearing hosts. In fact, primed 2C cells were only found in BP-SIY tumors but not BPC-SIY tumors. These results were confirmed using in vivo 2-photon microscopy of the tumor microenvironment. Taken together, these data provide strong evidence that up-regulation of tumor-intrinsic β-catenin is a strong mechanism of immune evasion even in the presence of immunologic memory. As such, mechanisms of immune surveillance and editing of tumors expand beyond antigen-loss but additionally via specific up-regulation of oncogene pathways. Moreover, tumor-intrinsic β-catenin activation likely can mediate resistance not only to checkpoint blockade but also T cell adoptive transfer.

Authors’ Affiliations

(1)
University of Chicago
(2)
The University of Chicago School of Medicine

Copyright

© Spranger et al. 2015

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

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