Tumor recurrence after chemoradiotherapy is challenging to overcome, and approaches to predict the recurrence remain elusive. Here, human cervical cancer tissues before and after concurrent chemoradiotherapy (CCRT) analyzed by single-cell RNA sequencing reveal that CCRT specifically promotes CD8⁺ T cell senescence, driven by atypical chemokine receptor 2 (ACKR2)⁺ CCRT-resistant tumor cells. Mechanistically, ACKR2 expression is increased in response to CCRT and is also upregulated through the ligation of CC chemokines that are produced by activated myeloid and T cells. Subsequently, ACKR2⁺ tumor cells are induced to produce transforming growth factor β to drive CD8⁺ T cell senescence, thereby compromising antitumor immunity. Moreover, retrospective analysis reveals that ACKR2 expression and CD8⁺ T cell senescence are enhanced in patients with cervical cancer who experienced recurrence after CCRT, indicating poor prognosis. Overall, we identify a subpopulation of CCRT-resistant ACKR2⁺ tumor cells driving CD8⁺ T cell senescence and tumor recurrence and highlight the prognostic value of ACKR2 and CD8⁺ T cell senescence for chemoradiotherapy recurrence.

The survival duration of elderly patients with epithelial ovarian carcinoma is shorter than that of their younger counterparts. This variation in survival duration is likely attributed to differences in the distribution of histological type or grade, International Federation of Gynecology and Obstetrics (FIGO) staging, and undertreatment, but this observation remains controversial. This study aimed to investigate the biological factors other than selection bias associated with the decreased survival of elderly patients with ovarian carcinoma. A total of 314 serous ovarian cancer (SOC) patients from Jiangsu Institute of Cancer Research (JICR, PRC) between 2002 and 2012 were retrospectively analyzed, and 774 cases from MD Anderson Cancer Center (MDACC, USA) between 1992 and 2012 were used for validation. The 8-hydroxy-2′-deoxyguanine (8-OHdG) concentration in leukocyte DNA was evaluated by using commercially available enzyme-linked immunosorbent assay kits, and tissue expression was assayed through immunohistochemistry. The associations between survival durations and covariates were assessed by using a Cox proportional hazards model and by conducting a log-rank test. Advanced age ≥ 65 years was correlated with high histological grade (p = 0.02), performance status (p = 0.03), primary treatment (p = 0.00), and suboptimal surgery outcome (p = 0.04) in SOC patients from JICR. Age, FIGO stage, histological grade, and optimal surgery were independently associated with the progression-free survival (PFS; p = 0.03, p = 0.03, p = 0.02, and p = 0.04, respectively) and overall survival (OS; p = 0.02, p = 0.04, p = 0.02, and p = 0.02, respectively) of the SOC patients from JICR. The 8-OHdG concentration in the leukocyte DNA was higher in the elderly patients than in the younger cases. The high 8-OHdG concentration in the leukocyte DNA indicated poorer median OS (30.0 months, confidence interval [CI]: 23.5–36.5 vs. 42.8 months, [CI] 38.3–47.2) and PFS (14.6 months, [CI] 11.9–17.2 vs. 18.9 months, [CI] 14.4–23.4) than those of their corresponding counterparts in the SOC patients who achieved a clinical complete response from primary treatment. Compared with younger cases, elderly patients with SOC were commonly characterized by high tumor grade, poor performance status, and undertreatment. High 8-OHdG concentration in leukocyte DNA was associated with advanced age and poor prognosis in SOC patients.

Background: Oxidative damage and DNA repair dysfunction are associated with carcinogenesis. 8-OHdG is one of the major oxidative DNA adducts. Present work aims to investigate whether the expression of 8-OHdG and its key repair gene hOGG1 play distinctive role in two types of serous ovarian cancer. Materials and methods: 8-OHdG level in DNA from tumor and matched tumor-adjacent normal tissue in 48 high-grade papillary serous carcinomas (HG-SOC), 24 low-grade papillary serous carcinomas (LG-SOC), 20 serous cystadenomas, and 16 non-tumor control ovaries was tested. The Cox proportional hazards model and the log-rank test were used to assess the associations between the 8-OHdG level in two types of serous cancer and patients’ survival. Real-time polymerase chain reaction and protein immunoblot were employed to detect hOGG1 mRNA and protein levels in tumor and adjacent normal tissues. Immunohistochemistry was used to determine the expression of hOGG1 and p53. Results: There was no difference of average 8-OHdG/10⁶dG DNA level either between HG-SOC (27.8 ± 8.9), LG-SOC (25.2 ± 7.4) and benign serous cystadenoma (26.5 ± 7.7, p = 0.35); or between the tumor-adjacent normal tissue of HG-SOC (18.8 ± 5.2), LG-SOC (21.4 ± 6.5), benign serous cystadenoma (20.5 ± 9.1) and non-tumor ovary (21.6 ± 4.9, p = 0.62). The 8-OHdG/10⁶dG level was significantly higher in tumor comparing to that in matched normal tissue adjacent to carcinoma in HG-SOC (1.52 ± 0.52, p = 0.02), but not in LG-SOC or benign serous cystadenoma. Increased level of 8-OHdG in tumor DNA was an independent factor of overall survival in serous ovarian carcinoma upon multivariate analysis (p < 0.01). Increased level of 8-OHdG in tumor DNA indicates poorer overall and progression-free survival durations than counterparts (47.3 vs 105.7 months and 13.5 vs 45.3 months, respectively). Protein levels of hOGG1 were remarkably decreased in HG-SOC (p < 0.01), but not in LG-SOC and serous cystadenoma compared with the tissue adjacent to carcinoma. A positive result on p53 immunostaining was associated with lower hOGG1 expression in HG-SOC (p = 0.04). Conclusion: Increased 8-OHdG level and decreased expression of hOGG1 in tumor were found in HG-SOC but not LG-SOC. Increased 8-OHdG level in tumor DNA was significantly associated with poorer overall survival and progression-free survival in serous ovarian carcinoma.

Background: There is no consensus regarding the management of ovarian cancer patients, who have shown complete clinical response (CCR) to primary therapy and have rising cancer antigen CA-125 levels but have no symptoms of recurrent disease. The present study aims to determine whether follow-up CA-125 levels can be used to identify the need for imaging studies and secondary cytoreductive surgery (CRS). Methods: We identified 410 ovarian cancer patients treated at The University of Texas MD Anderson Cancer Center between 1984 and 2011. These patients had shown CCR to primary therapy. Follow-up was conducted based on the surveillance protocol of the MD Anderson Cancer Center. We used the Cox proportional hazards model and log-rank test to assess the associations between the follow-up CA-125 levels and secondary CRS and survival duration. Results: The CA-125 level of 1.68 × nadir was defined as the indicator of recurrent disease (p < 0.001). The specificity and sensitivity of this criterion were 82.9% and 85.6%, respectively, and the median lead-time of the CA-125 biochemical progression prior to clinically-defined relapse was 31 days (ranging from 1 to 391 days). The median number of the negative imaging studies for the clinical relapse findings in patients with a CA-125 level of < 1.68 × nadir was 3 (ranging from 0 to 24 times). The increase of CA-125 level at relapse was an independent predictor of overall and progression free survival in patients who had shown CCR to primary therapy (p = 0.04 and 0.02 respectively). The overall and progression free survival durations in patients with a CA-125 level ≤ 1.68 × nadir at relapse (69.4 and 13.8 months) were longer than those with a CA-125 level > 1.68 × nadir at relapse (55.7 and 10.4 months; p = 0.04 and 0.01, respectively). The overall and progression free survival duration of patients with asymptomatic relapse and underwent a secondary CRS was longer than that of patients with symptomatic relapse (p = 0.02 and 0.04 respectively). Conclusions: The increase of serum CA-125 levels is an early warning of clinical relapse in ovarian cancer. Using CA-125 levels in guiding the treatment of patients with asymptomatic recurrent ovarian cancer, who have shown CCR to primary therapy, can facilitate optimal secondary CRS and extend the survival duration of the patients.