The Dynamic Alternation of Local and Systemic Tumor Immune Microenvironment During Concurrent Chemoradiotherapy of Cervical Cancer: A Prospective Clinical Trial

Purpose This work assessed local and systemic alternations of the tumor immune microenvironment during concurrent chemoradiation therapy (CCRT) of local advanced cervical cancer to estimate the optimal timing for immune therapy in relation to CCRT. Methods and Materials In this single-center prospective clinical trial, 55 patients with stage IIA through IVA cervical cancer were enrolled between December 2016 and November 2017. The median follow-up was 32.1 months. All patients received cisplatin concurrently with external beam radiation therapy combined with high-dose-rate brachytherapy. Tumor tissues and peripheral blood mononuclear cells (PBMCs) were collected before, during and after CCRT. We analyzed the changes in lymphocyte subpopulations, programmed death-1 (PD-1) and programmed cell death ligand 1 (PD-L1) expression, and the T cell receptor (TCR) repertoire that occurred throughout CCRT. Results The frequencies of CD4+ and PD-1+ T cells in PBMCs decreased after the start of CCRT, whereas that of inhibitory regulatory T cells increased. In the tumor tissues, CCRT decreased the numbers of CD4+ and CD8+ T cells and reduced the median percentage of positive cells expressing PD-L1 from 78.1% to 49.8%. As indicated by the numbers of unique clones, the TCRs of PBMCs exhibited greater diversity before CCRT than after CCRT. Greater TCR diversity in PBMCs before CCRT was associated with superior 30-month progression-free survival (hazard ratio [HR], 0.12; 95% confidence interval [CI], 0.04-0.39; P = .001) and overall survival (HR, 0.17; 95% CI, 0.04-0.68; P = .004). Conclusions CCRT for cervical cancer altered the tumor immune microenvironment by reducing CD4+ and CD8+ T lymphocyte populations, PD-1/PD-L1 expression, and TCR diversity. Higher TCR diversity in PBMCs before CCRT resulted in better survival and prognosis, indicating that CCRT might inhibit immune activation. Our results suggest that it might be more effective to administer immune checkpoint inhibitors before CCRT of cervical cancer rather than during or after CCRT. This work assessed local and systemic alternations of the tumor immune microenvironment during concurrent chemoradiation therapy (CCRT) of local advanced cervical cancer to estimate the optimal timing for immune therapy in relation to CCRT. In this single-center prospective clinical trial, 55 patients with stage IIA through IVA cervical cancer were enrolled between December 2016 and November 2017. The median follow-up was 32.1 months. All patients received cisplatin concurrently with external beam radiation therapy combined with high-dose-rate brachytherapy. Tumor tissues and peripheral blood mononuclear cells (PBMCs) were collected before, during and after CCRT. We analyzed the changes in lymphocyte subpopulations, programmed death-1 (PD-1) and programmed cell death ligand 1 (PD-L1) expression, and the T cell receptor (TCR) repertoire that occurred throughout CCRT. The frequencies of CD4+ and PD-1+ T cells in PBMCs decreased after the start of CCRT, whereas that of inhibitory regulatory T cells increased. In the tumor tissues, CCRT decreased the numbers of CD4+ and CD8+ T cells and reduced the median percentage of positive cells expressing PD-L1 from 78.1% to 49.8%. As indicated by the numbers of unique clones, the TCRs of PBMCs exhibited greater diversity before CCRT than after CCRT. Greater TCR diversity in PBMCs before CCRT was associated with superior 30-month progression-free survival (hazard ratio [HR], 0.12; 95% confidence interval [CI], 0.04-0.39; P = .001) and overall survival (HR, 0.17; 95% CI, 0.04-0.68; P = .004). CCRT for cervical cancer altered the tumor immune microenvironment by reducing CD4+ and CD8+ T lymphocyte populations, PD-1/PD-L1 expression, and TCR diversity. Higher TCR diversity in PBMCs before CCRT resulted in better survival and prognosis, indicating that CCRT might inhibit immune activation. Our results suggest that it might be more effective to administer immune checkpoint inhibitors before CCRT of cervical cancer rather than during or after CCRT.