Blocking of EphA2 on Endometrial Tumor Cells Reduces Susceptibility to V delta 1 Gamma-Delta T-Cell-Mediated Killing

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F65269705%3A_____%2F21%3A00074678" target="_blank" >RIV/65269705:_____/21:00074678 - isvavai.cz</a>

Výsledek na webu

<a href="https://www.frontiersin.org/articles/10.3389/fimmu.2021.752646/full" target="_blank" >https://www.frontiersin.org/articles/10.3389/fimmu.2021.752646/full</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.3389/fimmu.2021.752646" target="_blank" >10.3389/fimmu.2021.752646</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Blocking of EphA2 on Endometrial Tumor Cells Reduces Susceptibility to V delta 1 Gamma-Delta T-Cell-Mediated Killing

Popis výsledku v původním jazyce

Background Endometriosis is a common gynecological disease characterized by the presence of endometrial tissue outside the uterus causing chronic inflammation, severe pain, and infertility. However, the innate immunity of gamma-delta (gamma delta) T lymphocytes in endometriosis has not been characterized. Women with endometriosis present numerous endocrine and immune dysfunctions and elevated risk for endometrial, ovarian, and breast cancers. The tyrosine kinase EphA2 is often overexpressed in cancer including endometrial carcinoma.&lt;/p&gt; Methods We analyzed V delta 1 and V delta 2 gamma delta T cells in peripheral blood and paired peritoneal fluid samples in endometriosis patients (n = 19) and compared the counts with that of age- and sex-matched healthy donors (n = 33) using flow cytometry. V delta 1 and V delta 2 T cells isolated from healthy donors were used against KLE, RL-95, and Ishikawa endometrial tumor cells in 4 h flow cytometric cytotoxicity assays. The EphA2 blocking studies were performed using antibody, small-molecule inhibitor ALW-II-41-27, and the CRISPR/Cas9.&lt;/p&gt; Results We determined V delta 1 T cells substantially reduced in patients&apos; peripheral blood (p &lt; 0.01) and peritoneal fluid (p &lt; 0.001). No differences were found for circulating V delta 2 T cells compared with peritoneal fluid samples. We observed inherent cytotoxic reactivity of V delta 1 and V delta 2 gamma delta T lymphocytes against endometrial tumor cells. Importantly, we found reduced specific lysis of EphA2-positive cell lines KLE and RL-95 by V delta 1 T cells in the EphA2 antibody blocking studies and by the EphA2 inhibitor. Furthermore, V delta 1 T-cell-mediated killing was significantly decreased in RL-95 cell EPHA2 knockout. Finally, potent cytolytic activity exerted by V delta 1 T cells was significantly reduced in EPHA2 knockouts in renal A-498 and colon HT-29 carcinoma cell lines.&lt;/p&gt; Conclusions We determined variable levels of V delta 1 and V delta 2 gamma delta T cells in endometriosis patients. We observed inherent cytotoxic reactivity of gamma delta T-cell subsets against endometrial cell lines. Specifically, we found that blocking of EphA2 expression resulted in significant inhibition of endometrial tumor killing mediated by V delta 1 gamma delta T cells. These results suggest that EphA2 is involved in tumor cell lysis and contributes to susceptibility to V delta 1 gamma delta T cells cytotoxic reactivity.

Název v anglickém jazyce

Blocking of EphA2 on Endometrial Tumor Cells Reduces Susceptibility to V delta 1 Gamma-Delta T-Cell-Mediated Killing

Popis výsledku anglicky

Background Endometriosis is a common gynecological disease characterized by the presence of endometrial tissue outside the uterus causing chronic inflammation, severe pain, and infertility. However, the innate immunity of gamma-delta (gamma delta) T lymphocytes in endometriosis has not been characterized. Women with endometriosis present numerous endocrine and immune dysfunctions and elevated risk for endometrial, ovarian, and breast cancers. The tyrosine kinase EphA2 is often overexpressed in cancer including endometrial carcinoma.&lt;/p&gt; Methods We analyzed V delta 1 and V delta 2 gamma delta T cells in peripheral blood and paired peritoneal fluid samples in endometriosis patients (n = 19) and compared the counts with that of age- and sex-matched healthy donors (n = 33) using flow cytometry. V delta 1 and V delta 2 T cells isolated from healthy donors were used against KLE, RL-95, and Ishikawa endometrial tumor cells in 4 h flow cytometric cytotoxicity assays. The EphA2 blocking studies were performed using antibody, small-molecule inhibitor ALW-II-41-27, and the CRISPR/Cas9.&lt;/p&gt; Results We determined V delta 1 T cells substantially reduced in patients&apos; peripheral blood (p &lt; 0.01) and peritoneal fluid (p &lt; 0.001). No differences were found for circulating V delta 2 T cells compared with peritoneal fluid samples. We observed inherent cytotoxic reactivity of V delta 1 and V delta 2 gamma delta T lymphocytes against endometrial tumor cells. Importantly, we found reduced specific lysis of EphA2-positive cell lines KLE and RL-95 by V delta 1 T cells in the EphA2 antibody blocking studies and by the EphA2 inhibitor. Furthermore, V delta 1 T-cell-mediated killing was significantly decreased in RL-95 cell EPHA2 knockout. Finally, potent cytolytic activity exerted by V delta 1 T cells was significantly reduced in EPHA2 knockouts in renal A-498 and colon HT-29 carcinoma cell lines.&lt;/p&gt; Conclusions We determined variable levels of V delta 1 and V delta 2 gamma delta T cells in endometriosis patients. We observed inherent cytotoxic reactivity of gamma delta T-cell subsets against endometrial cell lines. Specifically, we found that blocking of EphA2 expression resulted in significant inhibition of endometrial tumor killing mediated by V delta 1 gamma delta T cells. These results suggest that EphA2 is involved in tumor cell lysis and contributes to susceptibility to V delta 1 gamma delta T cells cytotoxic reactivity.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30214 - Obstetrics and gynaecology

Projekt

<a href="/cs/project/NV19-05-00410" target="_blank" >NV19-05-00410: Úloha cytotoxických gamma-delta T buněk na terapeutické rezistenci a recidivě Glioblastoma Multiforme</a><br>

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)<br>I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2021

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Frontiers in Immunology

ISSN

1664-3224

e-ISSN

—

Svazek periodika

12

Číslo periodika v rámci svazku

OCT 7

Stát vydavatele periodika

CH - Švýcarská konfederace

Počet stran výsledku

12

Strana od-do

752646

Kód UT WoS článku

000710789400001

EID výsledku v databázi Scopus

2-s2.0-85117588473