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
  • 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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