Interleukin-21 can efficiently restore impaired antibody-dependent cell-mediated cytotoxicity in patients with oesophageal squamous cell carcinoma

Abstract

BACKGROUND: We previously reported that Trastuzumab-and Cetuximab-mediated antibody-dependent cell-mediated cytotoxicity (ADCC) in cancer patients was impaired in comparison with that in healthy donors because of NK-cell dysfunction. In this study, we evaluated whether IL-21 could improve the impairment of ADCC in patients with oesophageal squamous cell carcinoma (ESCC), as IL-21 was reported to have the ability to activate NK cells. METHODS: We examined Trastuzumab-and Cetuximab-mediated ADCC of peripheral blood mononuclear cells (PBMCs) or of enriched NK cells derived from ESCC patients (n ¼ 20) and healthy donors (n ¼ 16) in the presence of IL-21. We further analysed ADCC-related molecules (perforin, granzyme-B, and CD247) on NK cells in response to IL-21. RESULTS: Trastuzumab-and Cetuximab-mediated ADCC of PBMCs or of enriched NK cells was enhanced by the addition of IL-21 in a dose-dependent manner and the levels of ADCC enhanced by IL-21 in patients were high enough in comparison with those in healthy donors, paralleling the upregulation of CD247 on NK cells. CONCLUSION: IL-21 could efficiently restore impaired ADCC in ESCC patients with the upregulation of CD247 molecules.

Antibody-Dependent Cellular Cytotoxicity Activity of a Novel Anti–PD-L1 Antibody Avelumab (MSB0010718C) on Human Tumor Cells

“…In our in vitro system, pre-treating the PBMC effector cells overnight with IL2 did not increase the avelumab-induced ADCC activity (Supplementary Table S1). It has been shown that IL21 can enhance the in vitro ADCC activity of both trastuzumab and cetuximab (45). Studies are now emerging that IL15 can greatly enhance NK cells in both experimental systems and clinical studies (46, 47).…”

IL-15 and IL-2 increase Cetuximab-mediated cellular cytotoxicity against triple negative breast cancer cell lines expressing EGFR

“…One of the possibilities is the low proportion of CD3 -CD56 ? (NK cells) infiltrating CRC tumors [20] and the low functional capacity of these cells observed in cancer patients [21][22][23]. Therefore, if we could enhance the activity of NK cells, the efficacy of treatment with Cetuximab could be increased.…”

IL-21 and IL-12 Inhibit Differentiation of Treg and TH17 Cells and Enhance Cytotoxicity of Peripheral Blood Mononuclear Cells in Patients With Cervical Cancer

“…The mechanisms include a shift from a T helper 1 (T H 1)Ytype to a T H 2-type cytokine response, 1 dysfunction of cytotoxic CD8 + T cells and natural killer (NK) cells, induction of T regulatory (Treg) cells, and so on. 2 Among human CD4 + T cells, besides the traditional T H 1 and T H 2 helper cell subsets, 2 novel subsets have been identified, namely, Treg cells and T H 17 cells. T regulatory cells have been implicated in the progression of various tumors through obstruction of the development of effective antitumor immunity, 3 as Treg cells are found higher in the peripheral blood of cancer patients.…”

“…2,8 Interleukin 21 has been shown to be an important autocrine factor of T H 17 cells. 9 Interleukin 12 is known to be an NK cell stimulatory factor and a cytotoxic lymphocyte maturation factor 10 and inhibits Treg cell proliferation and activities.…”