2. Academic Validation
  3. JAK/Stat5-mediated subtype-specific lymphocyte antigen 6 complex, locus G6D (LY6G6D) expression drives mismatch repair proficient colorectal cancer

JAK/Stat5-mediated subtype-specific lymphocyte antigen 6 complex, locus G6D (LY6G6D) expression drives mismatch repair proficient colorectal cancer

  • J Exp Clin Cancer Res. 2019 Jan 22;38(1):28. doi: 10.1186/s13046-018-1019-5.
Guido Giordano 1 2,  Pietro Parcesepe 3,  Mario Rosario D'Andrea 4,  Luigi Coppola 4,  Tania Di Raimo 4,  Andrea Remo 5,  Erminia Manfrin 3,  Claudia Fiorini 3,  Aldo Scarpa 3,  Carla Azzurra Amoreo 6,  Fabiana Conciatori 7,  Michele Milella 7,  Francesca Pia Caruso 8 9,  Luigi Cerulo 8 9,  Almudena Porras 10 11,  Massimo Pancione 12 13
Affiliations

Affiliations

  • 1 Oncology Unit, Casa Sollievo della Sofferenza-IRCCS, San Giovanni Rotondo, Italy. giordano.guido81@gmail.com.
  • 2 Medical Oncology and Anatomic Pathology Unit, San Filippo Neri Hospital, Rome, Italy. giordano.guido81@gmail.com.
  • 3 Department of Diagnostics and Public Health - Section of Pathology, University and Hospital Trust of Verona, Verona, Italy.
  • 4 Medical Oncology and Anatomic Pathology Unit, San Filippo Neri Hospital, Rome, Italy.
  • 5 Pathology Unit, "Mater Salutis" Hospital AULSS9, Legnago (Verona), Italy.
  • 6 Pathology, IRCCS Regina Elena National Cancer Institute, Rome Italy, Via Elio Chianesi 53, 00144, Rome, Italy.
  • 7 Medical Oncology, IRCCS Regina Elena National Cancer Institute, Rome Italy, Via Elio Chianesi 53, 00144, Rome, Italy.
  • 8 Department of Sciences and Technologies, University of Sannio, Via Port'Arsa, 1182100, Benevento, Italy.
  • 9 Bioinformatics Laboratory, BIOGEM scrl, Ariano Irpino, Avellino, Italy.
  • 10 Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Complutense University Madrid, Madrid, Spain. maporras@ucm.es.
  • 11 Health Research Institute of the Hospital Clínico San Carlos (IdISSC), Madrid, Spain. maporras@ucm.es.
  • 12 Department of Sciences and Technologies, University of Sannio, Via Port'Arsa, 1182100, Benevento, Italy. massimo.pancione@unisannio.it.
  • 13 Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Complutense University Madrid, Madrid, Spain. massimo.pancione@unisannio.it.
PMID: 30670049 DOI: 10.1186/s13046-018-1019-5
Abstract

Background: Human microsatellite-stable (MSS) colorectal cancers (CRCs) are immunologically "cold" tumour subtypes characterized by reduced immune cytotoxicity. The molecular linkages between immune-resistance and human MSS CRC is not clear.

Methods: We used transcriptome profiling, in silico analysis, immunohistochemistry, western blot, RT-qPCR and immunofluorescence staining to characterize novel CRC immune biomarkers. The effects of selective antagonists were tested by in vitro assays of long term viability and analysis of kinase active forms using anti-phospho antibodies.

Results: We identified the lymphocyte antigen 6 complex, locus G6D (LY6G6D) as significantly overexpressed (around 15-fold) in CRC when compared with its relatively low expression in Other human solid tumours. LY6G6D up-regulation was predominant in MSS CRCs characterized by an enrichment of immune suppressive regulatory T-cells and a limited repertoire of PD-1/PD-L1 immune checkpoint receptors. Coexpression of LY6G6D and CD15 increases the risk of metastatic relapse in response to therapy. Both JAK-STAT5 and RAS-MEK-ERK cascades act in concert as key regulators of LY6G6D and Fucosyltransferase 4 (FUT4), which direct CD15-mediated immune-resistance. Momelotinib, an inhibitor of JAK1/JAK2, consistently abrogated the STAT5/LY6G6D axis in vitro, sensitizing MSS Cancer cells with an intact JAK-STAT signaling, to efficiently respond to trametinib, a MEK Inhibitor used in clinical setting. Notably, colon Cancer cells can evade JAK2/JAK1-targeted therapy by a reversible shift of the RAS-MEK-ERK pathway activity, which explains the treatment failure of JAK1/2 inhibitors in refractory CRC.

Conclusions: Combined targeting of STAT5 and MAPK pathways has superior therapeutic effects on immune resistance. In addition, the new identified LY6G6D antigen is a promising molecular target for human MSS CRC.

Keywords

Colorectal cancer; Immune resistance; LY6G6D; Microsatellite-stable.

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