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Whole Cancer Cell Vaccine Protects Ovarian Functions in Tumor-bearing Mice through Downregulating CXCL10

ABSTRACT: Your female patients with cancer will probably become sub-fertile or infertile even though some finally overcome the cancer through various therapies. Cancer immunotherapy is recently emerging as a promising novel therapy against cancer with high malignancy and lethality, but whether or not cancer immunotherapy affect female fertility is rarely known. In the present study, we employed MCA205 cells-xenografted B6 mice as model to investigate whether two popular immunotherapies, PD-1 monoclonal antibody (PD-1) and whole cancer cell vaccine (WCA), affect ovarian function. We found that MCA205 xenograft (M) conduced to decreased follicle numbers at each stage, decreased proliferation and increased apoptosis, decreased oocyte maturation rate and disrupted estrus cycle. WCA treatment significantly rescues the upper abnormalities while PD-1 didn't. Ovary RNA sequencing revealed that multiple DEGs (differentially-expressed genes) are involved in inflammation pathways. Next, cytokine microarray characterized CXCL10 with both biggest increment in M group and best rescue in WCA group. Next, CXCL10 antibody Immunoprecipitation in ovarian lysate and LC-MS baited the only receptor IL18R1. Next, we found that CXCL10 could at least impaired ovarian function through three pathways: it can increase ovarian inflammation through CXCL10→IL18R1→p-P65, induce ovarian fibrosis through CXCL10→IL18R1→p-JNK→COL1A1, and promote primordial follicle overactivation through CXCL10→IL18R1→p-AKT. Finally, we succeeded in rescuing ovarian function in M group through blocking the CXCL10→IL18R1 binding with CXCL10 antibody or a CXCL10-IL18R1 interface peptide. This study provided both mechanical evidences and translational strategies for whole cell vaccine in achieving dual functions, suppressing tumor progression meanwhile protecting ovarian function.

ORGANISM(S): Mus musculus

PROVIDER: GSE248829 | GEO | 2024/11/01

REPOSITORIES: GEO

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Project description:PD-0332991 is a selective inhibitor of the CDK4/6 kinases with the ability to block retinoblastoma (Rb) phosphorylation in the low nanomolar range. Here we investigate the role of CDK4/6 inhibition in human ovarian cancer. We examined the effects of PD-0332991 on proliferation, cell-cycle, apoptosis, and Rb phosphorylation using a panel of 40 established human ovarian cancer cell lines. Molecular markers for response prediction, including p16 and Rb, were studied using gene expression profiling, Western blot, and arrayCGH. Multiple drug effect analysis was used to study interactions with chemotherapeutic drugs. Expression of p16 and Rb was studied using immunohistochemistry in a large clinical cohort ovarian cancer patients. Concentration-dependent anti-proliferative effects of PD-0332991were seen in all ovarian cancer cell lines, but varied significantly between individual lines. Rb proficient cell lines with low p16 expression were most responsive to CDK4/6 inhibition. Copy number variations of CDKN2A, Rb, CCNE1, and CCND1 were associated with response to PD-0332991. CDK4/6 inhibition induced G0/G1 cell cycle arrest, blocked Rb phosphorylation in a concentration and time dependent manner, and enhanced the effects of chemotherapy. Rb proficiency with low p16 expression was seen in 97/262 (37%) of ovarian cancer patients and associated with adverse clinical outcome (progression free survival, adjusted relative risk 1.49, 95%CI 0.99-2.22, p =0.054). PD-0332991 shows promising biologic activity in ovarian cancer cell lines. Assessment of Rb and p16 expression may help select patients most likely to benefit from CDK4/6 inhibition in ovarian cancer. Gene expression of 40 individual ovarian cell lines relative to an ovarian cell line reference mix containing equal amounts of 41 ovarian cell lines (including OCC-1 which was later identified as originating from mouse). The expression data was correllated with cell line growth response to CDK 4/6 inhibitor PD-0332991 to identify genes associated with drug sensitivity and resistance.

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Whole Cancer Cell Vaccine Protects Ovarian Functions in Tumor-bearing Mice through Downregulating CXCL10

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