The cross talk between gastric cancer stem cells and the immune microenvironment: a tumor-promoting factor

Abstract

Cross talk between cancer cells and the immune system is determinant for cancer progression. Emerging evidence demonstrates that GC characteristics such as metastasis, treatment resistance, and disease recurrence are associated with a tumor subpopulation called gastric cancer stem cells (GCSCs). However, the specific interaction between GCSCs and the immune microenvironment is still under investigation. Although immune evasion has been well described for cancer stem cells (CSCs), recent studies show that GCSCs can also regulate the immune system and even benefit from it. This review will provide an overview of bidirectional interactions between CSCs and immune cells in GC, compiling relevant data about how CSCs can induce leukocyte reprogramming, resulting in pro-tumoral immune cells that orchestrate promotion of metastasis, chemoresistance, tumorigenicity, and even increase in number of cancer cells with stem properties. Some immune cells studied are tumor-associated macrophages (TAMs), neutrophils, Th17 and T regulatory (T_reg) cells, mesenchymal stem cells (MSCs), and cancer-associated fibroblasts (CAFs), as well as the signaling pathways involved in these pro-tumoral activities. Conversely, although there are cytotoxic leukocytes that can potentially eliminate GCSCs, we describe mechanisms for immune evasion in GCSCs and their clinical implications. Furthermore, we describe current available immunotherapy targeting GCSC-related markers as possible treatment for GC, discussing how the CSC-modified immune microenvironment can mitigate or inactivate these immunotherapies, limiting their effectiveness. Finally, we summarize key concepts and relevant evidence to understand the cross talk between GCSCs and the immune microenvironment as an important process for effective design of therapies against GCSCs that improve the outcome of patients with GC.

Keywords: Cancer microenvironment; Cancer stem cells; Cancer-associated immune cells; Cell reprogramming; Gastric cancer; Immunoregulation; Immunotherapy.

Fig. 1

Antigen-presenting cells in gastric cancer immunoregulation. CSC, cancer stem cell; TAM, tumor-associated macrophage; M2, TAM type M2; Neu, neutrophil; MSC, mesenchymal stem cell; CAF, cancer-associated fibroblast; EMT, epithelial-mesenchymal transition; VEGF, vascular endothelial growth factor; MIP-2, macrophage inflammatory protein-2; lncRNA, long non-coding RNA; 5′TP RNA, 5′-Triphosphate RNA. TAM-M2 and neutrophils promote the EMT phenotype in GC. CSCs in turn recruit pro-inflammatory neutrophils from the bone marrow, through an exosome-mediated mechanism. Cancer cells stimulate differentiation of mesenchymal cells towards CAFs, which favor stemness characteristics and metastasis, through the action of non-coding RNA-containing exosomes

Fig. 2

Lymphocytes and immune checkpoints in the gastric cancer immunoregulation. CSC, cancer stem cell; PCC, progenitor cancer cell; MSC, mesenchymal stem cell; Neu, neutrophil; NK, natural killer lymphocyte; VEGF, vascular endothelial growth factor; PGE2, prostaglandin E2; MIP-2, macrophage inflammatory protein-2. The interaction between MSCs and PCCs promotes lymphocyte differentiation towards the Th17 phenotype. Furthermore, interaction between MSCs and CSCs favors a T_reg phenotype. Differentiation of both, T_reg and Th17 lymphocytes, into an intermediate IL-17⁺FOXP3⁺ phenotype is possible, and the presence of this population has been shown to promote stemness in cancer cells. Expression of immune checkpoints can favor immune evasion in tumors, however, it can also stimulate stemness characteristics

Fig. 3

Stemness-related signaling pathways stimulated by the immune system. Neu, neutrophil; MSC, mesenchymal stem cell; CSC, cancer stem cell; EMT, epithelial mesenchymal transition; T_reg, T regulatory lymphocyte; Shh, Sonic hedgehog. The Notch pathway regulates the balance between Th17 and Treg. The immune microenvironment regulates tumoral process such as EMT and expression of stemness markers, as well as immune evasion