Improved migration of tumor ascites lymphocytes to ovarian cancer microenvironment by CXCR2 transduction
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Improved migration of tumor ascites lymphocytes to ovarian cancer microenvironment by CXCR2 transduction. / Idorn, Manja; Olsen, Maria; Halldórsdóttir, Hólmfrídur Rósa; Skadborg, Signe Koggersbøl; Pedersen, Magnus; Høgdall, Claus; Høgdall, Estrid; Met, Özcan; thor Straten, Per.
In: OncoImmunology, Vol. 7, No. 4, e1412029, 2018.Research output: Contribution to journal › Journal article › Research › peer-review
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T1 - Improved migration of tumor ascites lymphocytes to ovarian cancer microenvironment by CXCR2 transduction
AU - Idorn, Manja
AU - Olsen, Maria
AU - Halldórsdóttir, Hólmfrídur Rósa
AU - Skadborg, Signe Koggersbøl
AU - Pedersen, Magnus
AU - Høgdall, Claus
AU - Høgdall, Estrid
AU - Met, Özcan
AU - thor Straten, Per
PY - 2018
Y1 - 2018
N2 - Chemokines are essential mediators of cellular trafficking, interactions and tumor development. Though adoptive cell therapy (ACT) has been a tremendous success in the treatment of metastatic melanoma (MM), a major obstacle for successful ACT, is limited homing of effector T cells to immune suppressive tumor sites. We hypothesized that equipping T cells with chemokine receptors matching the chemokines of the tumor microenvironment, could improve tumor homing of T cells. T cells from malignant ascites (n = 13); blood from ovarian cancer (OC) patients (n = 14); and healthy donors (n = 13) were analyzed by flow cytometry. We found that FoxP3+ regulatory T cells accumulation in patients with OC associates with CCR4 expression. We characterized a chemokine profile of ascites chemokines, and expression of corresponding receptors on circulating T cells and tumor ascites lymphocytes (TALs). CCL22, CXCL9, CXCL10 and CXCL12 associated with enrichment of CCR4+, CCR5+, CXCR3+ and CXCR4+ T cells in ascites. Circulating T cells and TALs however did not express CXCR2, identifying CXCR2 as candidate for chemokine receptor transduction. TALs readily expressed IFNγ and TNFα upon stimulation despite the frequency decreasing with in vitro expansion. Lentiviral transduction of TALs (n = 4) with chemokine receptor CXCR2 significantly increased transwell migration of TALs towards rhIL8 and autologous ascites. The majority of expanded and transduced TALs were of a T effector memory subtype. This proof of concept study shows that chemokine receptor engineering with CXCR2 is feasible and improves homing of transduced TALs towards the OC microenvironment.
AB - Chemokines are essential mediators of cellular trafficking, interactions and tumor development. Though adoptive cell therapy (ACT) has been a tremendous success in the treatment of metastatic melanoma (MM), a major obstacle for successful ACT, is limited homing of effector T cells to immune suppressive tumor sites. We hypothesized that equipping T cells with chemokine receptors matching the chemokines of the tumor microenvironment, could improve tumor homing of T cells. T cells from malignant ascites (n = 13); blood from ovarian cancer (OC) patients (n = 14); and healthy donors (n = 13) were analyzed by flow cytometry. We found that FoxP3+ regulatory T cells accumulation in patients with OC associates with CCR4 expression. We characterized a chemokine profile of ascites chemokines, and expression of corresponding receptors on circulating T cells and tumor ascites lymphocytes (TALs). CCL22, CXCL9, CXCL10 and CXCL12 associated with enrichment of CCR4+, CCR5+, CXCR3+ and CXCR4+ T cells in ascites. Circulating T cells and TALs however did not express CXCR2, identifying CXCR2 as candidate for chemokine receptor transduction. TALs readily expressed IFNγ and TNFα upon stimulation despite the frequency decreasing with in vitro expansion. Lentiviral transduction of TALs (n = 4) with chemokine receptor CXCR2 significantly increased transwell migration of TALs towards rhIL8 and autologous ascites. The majority of expanded and transduced TALs were of a T effector memory subtype. This proof of concept study shows that chemokine receptor engineering with CXCR2 is feasible and improves homing of transduced TALs towards the OC microenvironment.
KW - ACT
KW - Adoptive cell therapy
KW - Ascites
KW - Chemokine receptor
KW - CXCR2
KW - Genetic engineering
KW - Ovarian Cancer
KW - Treg
KW - Tumor homing
U2 - 10.1080/2162402X.2017.1412029
DO - 10.1080/2162402X.2017.1412029
M3 - Journal article
C2 - 29632724
AN - SCOPUS:85039055638
VL - 7
JO - OncoImmunology
JF - OncoImmunology
SN - 2162-4011
IS - 4
M1 - e1412029
ER -
ID: 188361081