Phenotypic and Functional Dysregulated Blood NK Cells in Colorectal Cancer Patients Can Be Activated by Cetuximab Plus IL-2 or IL-15

Abstract

The clinical outcome of colorectal cancer (CRC) is associated with the immune response; thus, these tumors could be responsive to different immune therapy approaches. Natural killer (NK) cells are key antitumor primary effectors that can eliminate CRC cells without prior immunization. We previously determined that NK cells from the local tumor environment of CRC tumors display a profoundly altered phenotype compared with circulating NK cells from healthy donors (HD). In this study, we evaluated peripheral blood NK cells from untreated patients and their possible role in metastasis progression. We observed profound deregulation in receptor expression even in early stages of disease compared with HD. CRC-NK cells displayed underexpression of CD16, NKG2D, DNAM-1, CD161, NKp46, and NKp30 activating receptors, while inhibitory receptors CD85j and NKG2A were overexpressed. This inhibited phenotype affected cytotoxic functionality against CRC cells and interferon-γ production. We also determined that NKp30 and NKp46 are the key receptors involved in detriment of CRC-NK cells’ antitumor activity. Moreover, NKp46 expression correlated with relapse-free survival of CRC patients with a maximum follow-up of 71 months. CRC-NK cells also exhibited altered antibody-dependent cellular cytotoxicity function responding poorly to cetuximab. IL-2 and IL-15 in combination with cetuximab stimulated NK cell, improving cytotoxicity. These results show potential strategies to enhance CRC-NK cell activity.

An IL-15 superagonist/IL-15Rα fusion complex protects and rescues NK cell-cytotoxic function from TGF-β1-mediated immunosuppression

“…Moreover, against H460 and MDA-MB-231, TGF-β1 did not decrease avelumab-mediated ADCC activity. Consistent with our results, some studies also showed that TGF-β1 did not suppress cetuximab-mediated ADCC activity against tumor cells with high-EGFR expression (9, 42). On the contrary, in LNCap, which has low PD-L1 expression, TGF-β1 downregulated avelumab-mediated ADCC activity (0.7-fold) (Fig.…”

“…Intratumoral and peripheral NK cells from cancer patients may display phenotype alterations compared with NK cells from healthy donors (7, 42). Lee, et al, reported that the elevated level of plasma TGF-β1 correlated with low NKG2D expression on human NK cells from cancer patients (44).…”

Cetuximab Enhanced the Cytotoxic Activity of Immune Cells during Treatment of Colorectal Cancer

“…In summary, these data confirmed as it was previously demonstrated that cetuximab treatment could promote the cytotoxic activity of PBMCs and NK cells against tumor cells, which could be the underlying MoA of cetuximab against CRC cells [15]. …”

“…Studies have demonstrated that downregulation of expression of activating cells and upregulation of expression of inhibitory cells occur in the early stages of CRC [15]. The low functionality of NK cells could prevent NK cells from attacking and eliminating tumor cells in the circulation at early and advanced stages of the disease.…”

“…Some in vitro and mouse-model experiments have investigated the role of cetuximab in CRC treatment, but few studies have tried to determine the mechanism of action (MoA) of cetuximab during CRC treatment by analyzing the lymphocyte subsets of CRC patients [16, 19]. Mice-model experiments have suggested that cetuximab may target tumor cells by antibody-dependent cell-mediated cytotoxicity (ADCC) [20], and that cetuximab can intensify the ADCC antitumor activity of adoptive NK cells towards CRC with increased expression of the EGFR [15, 21-24]. Several studies have provided some information on how cetuximab acts on CRC in vitro , but the MoA of cetuximab during CRC treatment is not known due to a lack of in vivo studies.…”