Ex vivoexpanded human circulating Vδ1 γδT cells exhibit favorable therapeutic potential for colon cancer

Abstract

Gamma delta T (γδT) cells are innate-like lymphocytes with strong, MHC-unrestricted cytotoxicity against cancer cells and show a promising prospect in adoptive cellular immunotherapy for various malignancies. However, the clinical outcome of commonly used Vγ9Vδ2 γδT (Vδ2 T) cells in adoptive immunotherapy for most solid tumors is limited. Here, we demonstrate that freshly isolated Vδ1 γδT (Vδ1 T) cells from human peripheral blood (PB) exhibit more potent cytotoxicity against adherent and sphere-forming human colon cancer cells than Vδ2 T cells . We also develop an optimized protocol to preferentially expand Vδ1 T cells isolated from PB of both healthy donors and colon cancer patients by short-term culture with phytohemagglutinin (PHA) and interleukin-7 (IL-7). Expanded Vδ1 T cells highly expressed cytotoxicity-related molecules, chemokine receptors and cytokines with enhanced cytolytic effect against adherent and sphere-forming colon cancer cells in a cell-to-cell contact dependent manner. In addition, PHA and IL-7 expanded Vδ1 T cells showed proliferation and survival advantage partly through an IL-2 signaling pathway. Furthermore, expanded Vδ1 T cells also restrained the tumor growth and prolonged the tumor-burdened survival of human colon carcinoma xenografted mice. Our findings suggest that human PB Vδ1 T cells expanded by PHA and IL-7 are a promising candidate for anticancer adoptive immunotherapy for human solid tumors such as colon cancer.

Delta One T Cells for Immunotherapy of Chronic Lymphocytic Leukemia: Clinical-Grade Expansion/Differentiation and Preclinical Proof of Concept

“…One report showed positive responses and persistence in spleen and bone marrow upon ACT in mice up to 39 days after transfer (30), although it is not clear whether the recovered cells retained effector phenotype and if there was a wide distribution to other organs. Another report provided in vivo efficacy data in human colon carcinoma xenografted mice (34). Of note, this interesting study confirmed the greater antitumor efficacy of Vd1 þ cells over Vd2 þ gd T cells, which correlated with their expression of NCRs, suggesting that colon carcinoma could be an interesting target for DOT cells.…”

Elevation of Vδ1 T cells in peripheral blood and livers of patients with primary biliary cholangitis

“…No significant differences of the proportion of Vd1 T cells were found among the AR and HC groups. Although the liver is one of the organs that Vd1 T cells localize primarily in [24], we observed rare Vd1 T cells in control livers, corresponding with the distribution of murine Vd1 T cells [25]. Correlation analysis showed no correlation between Vd1 T cells and levels of serum ALT, AST, ALP, GGT, TBil and TBA of PBC.…”

Characterization of γδ T cells in patients with non-small cell lung cancer

“…The present study indicates that γδ T cells derived from the pleural effusion could be a source of adoptive γδ T cell immunotherapy in lung cancer. Unlike for Vδ2 T cells, which respond to phosphoantigens, there is no protocol concerning the expansion of Vδ1 + populations ex vivo, although a recent study indicated that PHA and IL-7 may be candidates to facilitate expansion of the Vδ1 subtype in circulating γδ T cells (13). However, the present authors have been unable to obtain a satisfactory result on the ex vivo expansion of Vδ1 or Vδ2 cells, either using PHA and IL-7 stimulation or zoledronic acid when using the γδ T cells isolated from pleural effusion in advanced NSCLC (Bao et al, unpublished data).…”

“…Unlike Vδ2 cells, Vδ1 cells do not respond to phosphoantigens, but are able to recognize the MHC class I chain-related molecules A and B (12). A recent study suggested that Vδ1 + T cells derived from the PB of normal donors are able to undergo ex vivo expansion by administration of phytohemagglutinin (PHA) and interleukin-7 (IL-7) (13); moreover, Vδ1 T cells exhibit more favorable antitumor activity than Vδ2 T cells in colon cancer (13). Ex vivo-expanded circulating γδ T cells represent a promising prospect in antitumor activities and are a potential candidate treatment for various malignancies, including non-small cell lung cancer (NSCLC).…”