암줄기세포의 특성 및 면역관문억제

Characteristics of Cancer Stem Cells and Immune Checkpoint Inhibition

Abstract

암줄기세포는 전이와 재발의 주요한 요인이 되는 자가재생능력, 분화할 수 있는 능력, 치료에 대한 저항성 및 암 형성 능력의 특성을 가진다. WNT/${\beta}$-catenin, Hedgehog, Notch, BMI1, BMP 및 TGF-${\beta}$와 같은 암줄기세포의 특성을 획득 및 유지할 수 있는 신호기전의 연구 결과가 존재하지만, 현재까지 선택적으로 암줄기세포를 표적할 수 있는 치료 전략은 미미하다. 최근, 면역관문억제제인 CTLA-4, PD-1/PD-L1 단일클론항체는 흑색종, 폐암, 췌장암 및 혈액암에 괄목할만한 임상 시험 결과를 나타냈으며, 긴 항암지속효과와 적은 부작용은 기존 항암제보다 개선 된 모습을 보였다. 또한 두경부편평상피암, 흑색종, 유방암 줄기세포를 선택적으로 제거 하였다. 위의 결과를 종합하면, 면역관문억제제는 이전 항암제에 비해 효과적인 항암전략이며, 동시에 암줄기세포를 선택적으로 제거할 수 있는 가능성을 시사한다. 따라서 본 리뷰에서는 암줄기세포와 면역관문억제제의 이해를 통해, 면역관문억제제의 암줄기세포 표적 가능성에 대해 고찰하고자 한다.

Cancer stem cells (CSCs), which are primarily responsible for metastasis and recurrence, have self-renewal, differentiation, therapeutic resistance, and tumor formation abilities. Numerous studies have demonstrated the signaling pathways essential for the acquisition and maintenance of CSC characteristics, such as WNT/${\beta}$-catenin, Hedgehog, Notch, B lymphoma Mo-MLV insertion region 1 homolog (BMI1), Bone morphogenetic protein (BMP), and TGF-${\beta}$ signals. However, few therapeutic strategies have been developed that can selectively eliminate CSCs. Recently, neutralizing antibodies against Cytotoxic T-lymphocyte associated protein 4 (CTLA-4) and Programmed cell death protein 1 (PD-1)/Programmed death-ligand 1 (PD-L1), immune checkpoint inhibitors (ICIs), have shown promising outcomes in clinical trials of melanoma, lung cancer, and pancreatic cancer, as well as in hematologic malignancies. ICIs are considered to outperform conventional anticancer drugs by maintaining long-lasting anti-cancer effects, with less severe side effects. Several studies reported that ICIs successfully blocked CSC properties in head and neck squamous carcinomas, melanomas, and breast cancer. Together, these findings suggest that novel and effective anticancer therapeutic modalities using ICIs for selective elimination of CSCs may be developed in the near future. In this review, we highlight the origin and characteristics of CSCs, together with critical signaling pathways. We also describe progress in ICI-mediated anticancer treatment to date and present perspectives on the development of CSC-targeting ICIs.

Fig. 1. The characteristics of cancer stem cells.

Fig. 2. Mechanism of immune checkpoints and inhibitors. A: CTLA-4 receptor expressed by T lymphocyte competes with CD28 to bind to CD80/CD86. CTLA-4, which has higher affinity than CD28, consequently inhibits CD28 so that function of T lymphocyte is blocked. B: T lymphocytes are activated by two consecutive signaling pathways. When antigen presenting cells present antigen via MHC class II, T lymphocytes bind through TCR, and subsequently CD28 receptor binds to CD80/CD86. As a result, T lymphocytes are activated to attack cancer cells. C: Cancer cells suppress T lymphocytes using PD-L1. Activated PD-1 signal reduces activity of T lymphocytes by inhibiting RAS and PI3K signaling pathways. D: Immune checkpoint inhibitors restore the activity of T lymphocytes through CTLA-4, PD-1 and PD-L1. As a result, T lymphocytes regain the function to eliminate cancer cells. (CTLA-4 inhibitor = Ipilimumab, PD-1 inhibitor = Nivolumab, PD-L1 inhibitor = Atezolizumab, Durvalumab and Avelumab).

Fig. 3. Multiple signaling molecules in immune checkpoint.

Table 1. List of immune checkpoint inhibitors currently being approved in clinical trial