γδ T cells and their clinical application in colon cancer

Abstract

In recent years, research has focused on colorectal cancer to implement modern treatment approaches to improve patient survival. In this new era, γδ T cells constitute a new and promising candidate to treat many types of cancer because of their potent killing activity and their ability to recognize tumor antigens independently of HLA molecules. Here, we focus on the roles that γδ T cells play in antitumor immunity, especially in colorectal cancer. Furthermore, we provide an overview of small-scale clinical trials in patients with colorectal cancer employing either in vivo activation or adoptive transfer of ex vivo expanded γδ T cells and suggest possible combinatorial approaches to treat colon cancer.

Keywords: MHC- unrestricted activation; colon rectal cancer; gamma delta T cells; immunotherapy; tumor.

Figure 1

Interaction between γδ T cells and colon cancer cells. Vδ1 and Vδ2 T cells conduct cytotoxic activities thanks to their ability to recognize stress antigens expressed by transformed cells, such as MHC class I-related molecules A and B (MICA/MICB) and UL16-binding proteins (ULBPs), via NKG2D receptor. Vδ1 T cells recognize self-glycolipids presented by CD1c and CD1d, and tumor cells through natural cytotoxicity receptors (NKp30, NKp44, NKp46). Vδ2 T cells recognize and respond to phosphoantigens (P-Ags), through unrestricted MHC manner, with two types I glycoproteins of the B7 family, butyrophilin (BTN)2A1 and BTN3A1. They interact with tumor cells through CD226 (DNAM-1)/CD155 (Nectin-2).

Figure 2

γδ T cells function against colon cancer cells. γδ T cells exert their cytotoxic functions through several mechanisms: induction of apoptotic cell death with Fas/TRAIL pathway, antibody-dependent cellular cytotoxicity (ADCC) with IgG/CD16 interaction, cytolytic granule (granzyme, perforin) polarization and degranulation, and proinflammatory cytokines (TNF-α, IFN-γ) production.

Figure 3

How to use γδ T cells in immunotherapy. Immunotherapeutic approaches based on Vγ9Vδ2 T cells involve two types of mechanisms: in vivo activation and adoptive transfer of ex vivo-expanded Vγ9Vδ2 T cells. The in vivo activation requires the administration of amino bisphosphonates (e.g., zoledronate), which induce the accumulation of endogenous phosphoantigens (P-Ags; such as IPP) by inhibiting the farnesyl pyrophosphate synthase of the mevalonate pathway and upregulating isoprenoid biosynthesis within cells. The ex vivo approach is based on the isolation of γδ T cells from peripheral blood mononuclear cells and the activation of Vγ9Vδ2 T cell, induced directly by natural (e.g., IPP and HMBPP) or synthetic (e.g., BrHPP) P-Ags plus IL-2 and the adoptive transfer.