Decreased invariant natural killer T-cell-mediated antitumor immune response in patients with gastric cancer.

Gastric cancer (GC) is the third most common cause of cancer-related death worldwide. Invariant natural killer T (iNKT) cells are innate-like cytotoxic T lymphocytes involved in tumor immune surveillance. They can be activated either through CD1d-presented glycolipid antigens recognized by their invariant T-cell receptor, cytokines or by sensing tumor-associated stress-induced ligands through the natural killer group 2, member D (NKG2D) receptor. Although the number and functionality of iNKT cells may be decreased in several types of cancer, here we show that GC patients presented a mild increase in iNKT cell frequencies and numbers in the blood compared with healthy donors. In GC patients, iNKT cells, expanded in vitro with α-galactosyl ceramide and stimulated with phorbol 12-myristate 13-acetate and ionomycin, produced higher levels of interleukin-2 and transforming growth factor-beta, while their capacity to degranulate remained preserved. Because tumor-derived epithelial cell adhesion molecule-positive epithelial cells did not display surface CD1d, and NKG2D ligands (NKG2DLs) were detected in the gastric tumor milieu, we envisioned a role for NKG2D in iNKT cell functions. Peripheral iNKT cells from GC patients and controls presented similar levels of NKG2D; nevertheless, the percentages of interferon-γ-producing and CD107a-positive iNKT cells from patients were reduced upon challenge with CD1d-negative, NKG2DL-positive K562 cells, suggesting a compromised response by iNKT cells in GC patients, which may not result from impaired NKG2D/NKG2DL signaling. The decreased response of iNKT cells may explain the fact that higher frequencies of circulating iNKT cells did not confer a survival benefit for GC patients. Therefore, functional impairment of iNKT cells in GC may contribute to tumor immune escape and favor disease progression.

Expresión génica de ligandos mica, micb y ulbp (1-6) del receptor NKG2D de células natural killer y metaloproteinasas adam10, adam17 y mmp14 en lineas celulares de cáncer de cervical / Gene expression of mica, micb and ulbp (1-6) ligands of the NKG2D receptor of natural killer cells and metalloproteinases adam10, adam17 and mmp14 in cells lines of cervical cancer

RESUMEN El CCU es la segunda causa de muerte en mujeres de nuestro país. Dentro de los primeros mecanismos de defensa del hospedero se encuentra la respuesta inmune de las células NK y su función lítica a expensas de su receptor activador NKG2D, el cual posee como ligandos mica, micb y ulbp (1-6), los cuales se expresan en células transformadas y/o infectadas por virus. Uno de los mecanismos de evasión por parte de la célula tumoral es el clivaje de estas proteínas a través de metaloproteinasas como adam10, adam17 y mmp14. Se analizó la expresión de estos ligandos y metaloproteinasas mediante PCR tiempo real, en lineas celulares de referencia para cáncer cervical como HeLa (positiva para VPH-18) y C33A (negativa para VPH). Se obtuvieron valores representativos de expresion relativa genica con diferencias significativas asi: mmp14 en linea HeLa (p= 0.006); y mica y ulbp-3 en la linea C33A (p= 0.020 y p=0.003 respectivamente). Por lo tanto, se podría sugerir que la expresión de mmp14 se encuentra posiblemente involucrados con la presencia de VPH causante del cancer cervical y la respuesta inmunne innata desarrollada.

ABSTRACT Cervical cancer is the second leading cause of death in women in our country. Within the first host defense mechanisms is the immune response of NK cells and their lytic function at the expense of its NKG2D receptor activator which has as ligands mica, micb and ulbp (1-6), which are expressed in transformed cells and / or virally infected. One of the mechanisms of evasion by the tumor cell is the cleavage of these proteins through metalloproteinases as adam10, adam17 and mmp14. We analyzed the expression of these ligands and metalloproteinases by real time PCR, in reference to cell lines HeLa cervical cancer (positive for HPV-18) and C33A (negative for HPV). We obtained representing relative gene expression with significant differences from the other lines of study as follows: mmp14 in HeLa (p = 0.006); and mica and ulbp-3 in C33A (p = 0.020 and p = 0.003 respectively). Thus one might suggest that the expression of mmp14 is possible involved with HPV presence causing high risk of cervical cancer and innate inmunne response developed.

Antígenos MICA y trasplante / MICA antigens and transplantation

Los antígenos leucocitarios humanos (HLA, del inglés human leukocyte antigens), codificados por los genes del complejo principal de histocompatibilidad (MHC, del inglés m ajor histocompatibility complex), actúan como inductores de las respuestas inmunitarias en el trasplante; sin embargo, los productos de los genes relacionados a cadenas MHC clase I (MIC, del inglés MHC class I chain-related genes), constituyen también uno de los blancos del rechazo. La familia de los genes MIC consta de siete miembros, de los cuales solo MICA y MICB son funcionales. Los transcriptos son glicoproteínas de superficie celular de 62 kDA que presentan homología en su secuencia con las moléculas HLA clase I y cuya función está relacionada con la inmunidad innata. En los órganos trasplantados ocurre un incremento en la expresión de los antígenos MICA como una señal temprana de "peligro" debido al trauma quirúrgico y la isquemia. Esta sobrexpresión antigénica puede llevar al rechazo mediado por anticuerpos anti-MICA que activan el complemento y por un incremento de la citotoxicidad debido a la estimulación en los linfocitos citolíticos naturales (NK, del inglés natural killer) y los linfocitos CD8+ &+ αß y γδ, del receptor conocido como NKG2D (NK grupo 2 miembro D(AU)

Human leukocyte antigens (HLA), encoded by major histocompatibility complex (MHC) genes, act as inducers of immune responses in transplantation. However, the products of the genes related to MHC class I chains (MIC) are also one of the targets of rejection. The family of MIC genes consists of seven members, of which only MICA and MICB are functional. Transcripts are cell surface glycoproteins of 62 kDa that exhibit homology in sequence with HLA class I molecules and whose function is related to innate immunity. In transplanted organs an increase in the expression of MICA antigens occurs as an early sign of "danger" due to surgical trauma and ischemia. This antigenic overexpression can lead to rejection mediated by complement-activating anti-MICA antibodies and by increased cytotoxicity due to stimulation in natural killer (NK) lymphocytes and CD8 + + αß and γδ lymphocytes. Receptor known as NKG2D (NK group 2 member D)(AU)