Far Beyond Cancer Immunotherapy: Reversion of Multi-Malignant Phenotypes of Immunotherapeutic-Resistant Cancer by Targeting the NANOG Signaling Axis

Abstract

Cancer immunotherapy, in the form of vaccination, adoptive cellular transfer, or immune checkpoint inhibitors, has emerged as a promising practice within the field of oncology. However, despite the developing field's potential to revolutionize cancer treatment, the presence of immunotherapeutic-resistant tumor cells in many patients present a challenge and limitation to these immunotherapies. These cells not only indicate immunotherapeutic resistance, but also show multi-modal resistance to conventional therapies, abnormal metabolism, stemness, and metastasis. How can immunotherapeutic-resistant tumor cells render multi-malignant phenotypes? We reasoned that the immune-refractory phenotype could be associated with multi-malignant phenotypes and that these phenotypes are linked together by a factor that acts as the master regulator. In this review, we discussed the role of the embryonic transcription factor NANOG as a crucial master regulator we named "common factor" in multi-malignant phenotypes and presented strategies to overcome multi-malignancy in immunotherapeutic-resistant cancer by restraining the NANOG-mediated multi-malignant signaling axis. Strategies that blunt the NANOG axis could improve the clinical management of therapy-refractory cancer.

Keywords: Common factor; Immunotherapy; Multi-malignant phenotypes; NANOG; Therapy-refractory cancer.

Figure 1. Emerging trends in the cancer immunotherapy. Cancer immunotherapy induces the patient's immune system's ability to recognize and kill tumor cells through tumor-specific Ags, tumor-associated Ags, and killer T cells. Immunotherapy can be materialized by vaccination or ACT, involving the transfer of CTLs that have been expanded to target tumor Ags. Recently, ICB therapy has taken the center stage in cancer treatment to address the ability of tumors to evade the immune system.

MART1, melanoma Ag recognized by T cells 1; NY-ESO-1, cancer/testis Ag 1; HPV, human papillomavirus; CAR, chimeric Ag receptor.

Figure 2. Concept of common factor which regulates multi-malignant phenotypes. Phenotypes common to stem-like tumor cells and immunotherapeutic-resistant tumor cells provide a first clue to identify a common factor that confers the multi-malignant phenotypes.

Figure 3. Key targets for overcoming NANOG-mediated multi-malignancy. Diagrammatic representation of the NANOG signaling axis, which trigger the multi-malignant properties of tumor cells, and different therapeutic strategies to target the NANOG axis.

TWIST1, twist-related protein 1; MMP, matrix metallopeptidase; HIF-1, hypoxia-inducible factor-1; MCL1, myeloid cell leukemia 1; BMI1, B lymphoma Mo-MLV insertion region 1 homolog.