IL-2- or IL-15-activated NK cells enhance Cetuximab-mediated activity against triple-negative breast cancer in xenografts and in breast cancer patients

Abstract

Triple-negative breast cancer (TNBC) patients do not benefit from target-specific treatments and is associated with a high relapse rate. Epidermal growth factor receptor is frequently expressed in TNBC and is a candidate for new therapies. In this work, we studied Cetuximab-mediated immune activity by NK cells. Thirteen activating/inhibitory receptors were examined on peripheral blood and tumor infiltrating NK cells. NK-cell functionality was evaluated using as effectors tumor-modulated NK cells and NK cells from patients. We evaluated the treatment with Cetuximab plus IL-2 or IL-15 in vivo in TNBC xenografts. Tumor NK-cells receptor profile showed upregulation of inhibitory receptors and downregulation of activating ones. Tumor-modulated NK cells were less cytotoxic. They could perform antibody-dependent cellular cytotoxicity (ADCC) triggered by Cetuximab, although impaired, it could still be restored by stimulation with IL-2 or IL-15. Patients with advanced disease displayed diminished levels of ADCC compared to healthy volunteers. ADCC was restored and potentiated with both cytokines, which were also effective in enhancing the therapeutic activity of Cetuximab in vivo. The combination of Cetuximab with IL-15 and IL-2 may be considered an attractive therapeutic approach to enhance the clinical efficacy of Cetuximab in TNBC.

IL-15 Deficient Tax Mice Reveal a Role for IL-1α in Tumor Immunity

“…The combination of IL-15 and cetuximab increased ADCC activity against triple negative breast cancer cell lines and enhanced cetuximab efficacy against HER1-positive head and neck cancer. [44], [45] IL-15 has also been shown to enhance rituximab-dependent cytotoxicity against chronic lymphocytic leukemia cells. [46] Moreover, the combination of IL-15 and anti-CD40 is more efficacious than either therapy alone in mouse models of metastatic colon cancer or metastatic renal cell carcinoma.…”

Phase II Study of Adjuvant Immunotherapy with the CSF-470 Vaccine Plus Bacillus Calmette–Guerin Plus Recombinant Human Granulocyte Macrophage-Colony Stimulating Factor vs Medium-Dose Interferon Alpha 2B in Stages IIB, IIC, and III Cutaneous Melanoma Patients: A Single Institution, Randomized Study

“…NK cells were tested for degranulating activity (CD107a membrane expression in the CD3 − CD56 + population) by flow cytometry, using canonical K562 cells (ATCC, CCL-243) (38) or MelC (non-irradiated CM cells composing CSF-470 vaccine: MEL-XY1, MEL-XY2, MEL-XY3, and MEL-XX4 cell lines) as targets in a 10:1 ratio as previously described (39). All samples were acquired on a BD FACSCalibur using Cellquest Pro software (BD Biosciences, Franklin Lakes, NJ, USA) and analyzed with FlowJo 7.6.2 software (FlowJo, Ashland, OR, USA).…”

The immune system and inflammation in breast cancer

“…Immunization against Stat3 in a mouse breast cancer xenograft model elicits strong antitumor immunity through memory CD4+ T cell dependent NK cell mediated cytotoxicity (Tkach et al, 2012). IL-2 or IL-15-activated NK cells potentiate the activity of cetuximab against triple negative breast cancer (Roberti et al, 2012). Stimulation of NK cells with a CD137-specific antibody enhances antibody-dependent cellular cytotoxicity (ADCC) and results in enhanced efficacy of trastuzumab against HER2+ breast cancer cells (Kohrt et al, 2012).…”