Targeting ALCAM in the cryo-treated tumour microenvironment successfully induces systemic anti-tumour immunity

Chie Kudo-Saito, Takafumi Fuwa, Yutaka Kawakami

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Cryoablative treatment has been widely used for treating cancer. However, the therapeutic efficacies are still controversial. The molecular mechanisms of the cryo-induced immune responses, particularly underlying the ineffectiveness, remain to be fully elucidated. In this study, we identified a new molecular mechanism involved in the cryo failure. We used cryo-ineffective metastatic tumour models that murine melanoma B16-F10 cells were subcutaneously and intravenously implanted into C57BL/6 mice. When the subcutaneous tumours were treated cryoablation on day 7 after tumour implantation, cells expressing activated leucocyte cell adhesion molecule (ALCAM/CD166) were significantly expanded not only locally in the treated tumours but also systemically in spleen and bone marrow of the mice. The cryo-induced ALCAM+ cells including CD45- mesenchymal stem/stromal cells, CD11b+Gr1+ myeloid-derived suppressor cells, and CD4+Foxp3+ regulatory T cells significantly suppressed interferon γ production and cytotoxicity of tumour-specific CD8+ T cells via ALCAM expressed in these cells. This suggests that systemic expansion of the ALCAM+ cells negatively switches host-immune directivity to the tumour-supportive mode. Intratumoural injection with anti-ALCAM blocking monoclonal antibody (mAb) following the cryo treatment systemically induced tumour-specific CD8+ T cells with higher cytotoxic activities, resulting in suppression of tumour growth and metastasis in the cryo-resistant tumour models. These suggest that expansion of ALCAM+ cells is a determinant of limiting the cryo efficacy. Further combination with an immune checkpoint inhibitor anti-CTLA4 mAb optimized the anti-tumour efficacy of the dual-combination therapy. Targeting ALCAM may be a promising strategy for overcoming the cryo ineffectiveness leading to the better practical use of cryoablation in clinical treatment of cancer.

Original languageEnglish
Pages (from-to)54-61
Number of pages8
JournalEuropean Journal of Cancer
Volume62
DOIs
Publication statusPublished - 2016 Jul 1

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Keywords

  • ALCAM
  • Cryoablation
  • Immune checkpoint inhibitor
  • Immunosuppression
  • Mesenchymal stem cell

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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