The Interplay between Integrins and Immune Cells as a Regulator in Cancer Immunology

Abstract

Integrins are a group of heterodimers consisting of α and β subunits that mediate a variety of physiological activities of immune cells, including cell migration, adhesion, proliferation, survival, and immunotolerance. Multiple types of integrins act differently on the same immune cells, while the same integrin may exert various effects on different immune cells. In the development of cancer, integrins are involved in the regulation of cancer cell proliferation, invasion, migration, and angiogenesis; conversely, integrins promote immune cell aggregation to mediate the elimination of tumors. The important roles of integrins in cancer progression have provided valuable clues for the diagnosis and targeted treatment of cancer. Furthermore, many integrin inhibitors have been investigated in clinical trials to explore effective regimens and reduce side effects. Due to the complexity of the mechanism of integrin-mediated cancer progression, challenges remain in the research and development of cancer immunotherapies (CITs). This review enumerates the effects of integrins on four types of immune cells and the potential mechanisms involved in the progression of cancer, which will provide ideas for more optimal CIT in the future.

Keywords: cancer; cancer immunotherapy; immune cells; immunity; integrins.

Figure 1

Integrins and their 4 categories of ligands; 18 α subunits and 8 β subunits constitute 24 integrins in humans, which can be divided into 4 categories according to their receptors. They are RGD receptors, leucocyte-specific receptors, collagen receptors, and laminin receptors. RGD: Arg-Gly-Asp.

Figure 2

Summary diagram of the effects of integrins in immune cells. Integrins can mediate several classical signaling pathways, including PI3K/AKT/mTOR, ILK/Rac1, and Fas/FasL. Activation of these specific pathways leads to a cascade reaction inducing the characteristics of immune cells, including proliferation, survival, migration, adhesion, and immunotolerance. FN: Fibronectin, GM-CSF Receptor: Granulocyte-macrophage colony-stimulating factor receptor, FAK: Focal adhesion kinase, PI3K: Phosphatidylinositol 3-phosphokinase, AKT: Protein kinase B, mTOR: Mammalian target of rapamycin, ILK: Integrin-linked kinase, Rac1: Rac Family Small GTPase, Fas: TNF receptor superfamily, FasL: Ligand of TNF receptor superfamily, PIP2: phosphatidylinositol (1,2,3) -triphosphate, Arp2/3: Actin nucleating protein complex, WASP: Wiscott aldridge syndrome protein, MRTF-A: Myocardin-related transcription factor-A, SRF: Serum response factor, SFK: SRC-Family protein tyrosine kinase, VCAM-1: Vascular cell adhesion molecule 1, ICAM-1: intercellular adhesion molecule 1, MadCAM1: Mucosal address in cell-adhesion molecule-1, Lck: Protein tyrosine kinase, ZAP-70: Zeta chain associated protein of 70 kDa, PKC: Protein kinase C, NF-kB: Nuclear factor-k-gene binding.

Figure 3

Three main mechanisms of positive modulation of integrins on cancer development. (A): Evading growth suppressor: Integrins can achieve evading growth suppressor by promoting cancer cell proliferation, differentiation, aggregation, and angiogenesis in the tumor microenvironment (TME). Under the influence of thyroid hormone, αVβ3 Integrins promote the proliferation and angiogenesis of the malignant T cell. The cytokines IL-1β and SDF-1α induce α4β1 integrins to interact with talin and paxillin to facilitate tumor growth. β4 integrins promote the differentiation of cancer stem cells into tumor cells. (B): Invasion and metastasis: Integrins mediate the invasion and metastasis of different types of cancer cells to other sites, leading to disease deterioration. β2 integrins and αV integrins promote, respectively, the invasion and metastasis of B-cell acute lymphoblastic leukemia cells and gastrointestinal cancer cells. αV integrins on the surface of epithelial cells can reshape the TME via activating TGF-β. The cancer B-cell in B-cell chronic lymphocytic leukemia (B-CLL) increases its survival and invasion by the activation of αLβ2 and α4β1 integrins via the JAK2 pathway. (C): Immune tolerance: Part of integrins on cancer cells inhibit the function of immune cells from achieving immune tolerance. αVβ3 integrins on the drug-resistant cancer cells inhibit the function of DCs via ATM/Chk2 and NFKB-mediated pathways. αVβ3 and αV integrins induce the process of TGF-β and TGFBR binding to suppress the immune killing effect of CD8+ T cell and NK cell, respectively. α4 integrins activated by PI3Kγ induce the polarization and aggregation of myeloid-derived suppressor cells (MDSCs) and TAMs to inhibit T-cell-mediated anti-tumor immune responses. In human T-cell acute lymphoblastic leukemia (ALL), β1 integrins activate the ABCC1 drug transporter of adriamycin via the PYK2 pathway. TH: Thyroid hormone, SDF-1α: Stromal cell-derived growth factor 1 alpha, DCs: Dendritic cells, NK cell: Natural killer cell, TGFBR: TGF-β receptor, MDSC: myeloid-derived suppressor cell, TAM: Tumor-associated macrophage, PYK2: Proline-rich tyrosine kinase 2.

Figure 4

Negative modulation of integrins on cancer development. Integrins can serve as an immune target for DCs to promote antigen presentation. By interacting with several signaling molecules, integrins facilitate the migration, aggregation, and killing of immune cells, including DCs, T cells, NK cells, and macrophages. DCs: αVβ3 integrins on drug-resistant cancer cells have increased expression for ATM/Chk2-and NF-κB-mediated pathways and act as the immune target of DCs. T cell: αLβ2 integrins on CD8+ T cell and αEβ7 integrins on CD3+CD8+ TRM separately induce the accumulation of CD8+ T cell and CD3+CD8+ TRM at the cancer region and promote the binding between TCR and cancer cell to result in cancer cell apoptosis. αEβ7 integrins on CD8+ T cells are activated by TGF-β via phosphorylated ILK and facilitate the aggregation of CD8+ T cells to cancer islets. NK cell: αLβ2 and αV integrins can enhance the cytotoxicity of NK cells by promoting the adhesion between NK cells and tumor cells and promoting ADCC, respectively. Macrophage: The expression of αL and αX integrins are promoted by inflammatory factors, which inhibit the amount of CD47 on cancer cells, thus preventing the function of checkpoint SIRPa-CD47. The signal of SPON2-α4β1 on M1-like macrophage activates both RhoA and Rac1 to facilitate its aggregation. Conversely, the signal of SPON2-α5β1 on HCC cells inhibits the aggregation of HCC cells by suppressing RhoA. CD3+CD8+ TRM: CD3+CD8+ tissue-resident memory T cells, NK cell: Natural killer cell, DC: Dendritic cell, TGFBR: TGF-β receptor, PKB: Protein kinase B, ILK: Integrin-linked kinase, ADCC: Antibody-dependent cell-mediated cytotoxicity, HCC: Hepatoma carcinoma cell.