title: 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.
authors: Fundación Instituto Leloir-IIBBA, Ciudad Autónoma de Buenos Aires , Buenos Aires , Argentina.
authors: Yamila Sol
authors: YS
authors: Rocca
authors: Centro de Investigaciones Oncológicas CIO-FUCA, Ciudad Autónoma de Buenos Aires , Buenos Aires , Argentina.
authors: María Paula
authors: MP
authors: Roberti
authors: Centro de Investigaciones Oncológicas CIO-FUCA, Ciudad Autónoma de Buenos Aires , Buenos Aires , Argentina.
authors: Estefanía Paula
authors: EP
authors: Juliá
authors: Centro de Investigaciones Oncológicas CIO-FUCA, Ciudad Autónoma de Buenos Aires , Buenos Aires , Argentina.
authors: María Betina
authors: MB
authors: Pampena
authors: Instituto Alexander Fleming, Ciudad Autónoma de Buenos Aires , Buenos Aires , Argentina.
authors: Luisina
authors: L
authors: Bruno
authors: Instituto Alexander Fleming, Ciudad Autónoma de Buenos Aires , Buenos Aires , Argentina.
authors: Sergio
authors: S
authors: Rivero
authors: Instituto Alexander Fleming, Ciudad Autónoma de Buenos Aires , Buenos Aires , Argentina.
authors: Eduardo
authors: E
authors: Huertas
authors: Instituto Alexander Fleming, Ciudad Autónoma de Buenos Aires , Buenos Aires , Argentina.
authors: Fernando
authors: F
authors: Sánchez Loria
authors: Instituto Alexander Fleming, Ciudad Autónoma de Buenos Aires , Buenos Aires , Argentina.
authors: Alejandro
authors: A
authors: Pairola
authors: UMRS-1160, Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France; U1160, Université Paris Diderot, Sorbonne Paris Cité, Paris, France.
authors: Anne
authors: A
authors: Caignard
authors: Fundación Instituto Leloir-IIBBA, Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina; Centro de Investigaciones Oncológicas CIO-FUCA, Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina; Instituto Alexander Fleming, Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina.
authors: José
authors: J
authors: Mordoh
authors: Centro de Investigaciones Oncológicas CIO-FUCA, Ciudad Autónoma de Buenos Aires , Buenos Aires , Argentina.
authors: Estrella Mariel
authors: EM
authors: Levy
keywords: IL-15; IL-2; NKp30; NKp46; cetuximab; colorectal cancer; natural killer cells