Malignant ascites enhance γδ T cell cytotoxicity towards ovarian cancer via modulating chemokines secretion from the cancer cells that recruits γδ T cells

Abstract

Ovarian cancer patients usually develops peritoneal metastasis and malignant ascites in the advanced stages, which form immuno-suppressive tumor microenvironments that limit the efficacy of immuno-therapies. However, during our previous research trying to develop a {gamma}{delta} T cell-based cell therapy, we noticed that the malignant ascites may enhance the cytotoxicity of {gamma}{delta} T cells towards ovarian cancer cells. Herein, in this work we showed that the phenomenon is real and the low molecular weight components in the ascites act on the cancer to promote the killing by {gamma}{delta} T cells. Transcriptome analysis and in vitro experiments revealed that the malignant ascites induce the secretion of chemokines CXCL2 and CXCL8 by ovarian cancer cells, which recruits {gamma}{delta} T cells through the chemokine receptors CXCR1 and CXCR2, to enhance the cytotoxicity of {gamma}{delta} T cells. Metabolomics analysis discovered compounds that are responsible for the enhancement of {gamma}{delta} T cell cytotoxicity, one of which follows the aforementioned mechanism, while other compounds reflect undiscovered mechanisms. Overall, we presented the positive side of the malignant ascites in anti-tumor immunity, revealed the underlining mechanisms and at least partially interpreted the molecular basis. Our work thus provides new insights into the development of cell therapies for ovarian cancer.