2. Academic Validation
  3. Highly immunogenic cancer cells require activation of the WNT pathway for immunological escape

Highly immunogenic cancer cells require activation of the WNT pathway for immunological escape

  • Sci Immunol. 2021 Nov 12;6(65):eabc6424. doi: 10.1126/sciimmunol.abc6424.
Yoshiko Takeuchi 1 2,  Tokiyoshi Tanegashima 1 3,  Eiichi Sato 4,  Takuma Irie 1,  Atsuo Sai 1,  Kota Itahashi 1,  Shogo Kumagai 1 5,  Yasuko Tada 1,  Yosuke Togashi 1,  Shohei Koyama 1 2,  Esra A Akbay 6,  Takahiro Karasaki 7,  Keisuke Kataoka 8 9,  Soichiro Funaki 10,  Yasushi Shintani 10,  Izumi Nagatomo 2,  Hiroshi Kida 2,  Genichiro Ishii 11,  Tomohiro Miyoshi 12,  Keiju Aokage 12,  Kazuhiro Kakimi 6,  Seishi Ogawa 9,  Meinoshin Okumura 10,  Masatoshi Eto 3,  Atsushi Kumanogoh 2,  Masahiro Tsuboi 12,  Hiroyoshi Nishikawa 1 5
Affiliations

Affiliations

  • 1 Division of Cancer Immunology, Research Institute/Exploratory Oncology Research & Clinical Trial Center (EPOC), National Cancer Center, Tokyo/Chiba, Japan.
  • 2 Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, Osaka, Japan.
  • 3 Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
  • 4 Department of Pathology, Institute of Medical Science, Tokyo Medical University, Tokyo, Japan.
  • 5 Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
  • 6 Department of Pathology, University of Texas Southwestern Medical Center, Dallas TX, USA.
  • 7 Department of Immunotherapeutics, University of Tokyo Hospital, Tokyo, Japan.
  • 8 Division of Molecular Oncology, Research Institute, National Cancer Center, Tokyo, Japan.
  • 9 Department of Pathology and Tumor Biology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
  • 10 Department of General Thoracic Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.
  • 11 Division of Pathology, National Cancer Center Hospital East, Chiba, Japan.
  • 12 Department of Thoracic Surgery, National Cancer Center Hospital East, Chiba, Japan.
PMID: 34767457 DOI: 10.1126/sciimmunol.abc6424
Abstract

PD-1 blockade exerts antitumor effects by reinvigorating tumor antigen–specific CD8+ T cells. Whereas neoantigens arising from gene alterations in Cancer cells comprise critical tumor antigens in antitumor immunity, a subset of non–small cell lung cancers (NSCLCs) harboring substantial tumor mutation burden (TMB) lack CD8+ T cells in the tumor microenvironment (TME), which results in resistance to PD-1 blockade therapy. To overcome this resistance, clarifying the mechanism(s) impairing antitumor immunity in highly mutated NSCLCs is an urgent issue. Here, we showed that activation of the Wnt/β-catenin signaling pathway contributed to the development of a noninflamed TME in tumors with high TMB. NSCLCs that lacked immune cell infiltration into the TME despite high TMB preferentially up-regulated the Wnt/β-catenin pathway. Immunologic assays revealed that those patients harbored neoantigen-specific CD8+ T cells in the peripheral blood but not in the TME, suggesting impaired T cell infiltration into the TME due to the activation of Wnt/β-catenin signaling. In our animal models, the accumulation of gene mutations in Cancer cells increased CD8+ T cell infiltration into the TME, thus slowing tumor growth. However, further accumulation of gene mutations blunted antitumor immunity by excluding CD8+ T cells from tumors in a Wnt/β-catenin signaling-dependent manner. Combined treatment with PD-1 blockade and Wnt/β-catenin signaling inhibitors induced better antitumor immunity than either treatment alone. Thus, we propose a mechanism-oriented combination therapy whereby immune checkpoint inhibitors can be combined with drugs that target cell-intrinsic oncogenic signaling pathways involved in tumor immune escape.

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