Reversal of the immunosuppressive tumor microenvironment via platinum-based neoadjuvant chemotherapy in cervical cancer

Background Immunotherapy favors patients with tumors;however,only 3-26.3%of patients with cervical cancer benefit from single-agent immune checkpoint inhibitors.Combined immunotherapy and chemotherapy has been explored against tumor;however,the combination remains controversial.This study aimed to investigate the tumor immune microenvironment(TIME)and the effects of platinum-based neoadjuvant chemotherapy(NACT)in cervical cancer to identify the clinical value of combining chemotherapy with immunotherapy.Methods Multiplex immunohistochemistry(IHC)with 11 markers(cluster of differentiation[CD]3,CD8,CD4,CD11c,CD68,forkhead box P3[Foxp3],programmed cell death 1[PD-1],programmed cell death 1 ligand 1[PD-L1],indoleamine 2,3-dioxygenase[IDO],cyclin-dependent kinase inhibitor 2A[p16],and cytokeratin[CK])was performed to evaluate TIME from 108 matched pre-and post-NACT cervical cancer samples.The mechanism of antitumor immunity triggered by NACT was explored using RNA sequencing(RNA-seq)from four paired samples and subsequently verified in 41 samples using IHC.Results The infiltration rate of the CD8^(+)T cells in treatment-naive cervical cancer was 0.73%,and those of Foxp3^(+)regulatory T cells(Tregs)and IDO^(+)cells were 0.87%and 17.15%,respectively.Moreover,immunoreactive T cells,dendritic cells,and macrophages were more in the stromal than the intratumor region.NACT increased dendritic,CD3^(+)T,CD8^(+)T,and CD4^(+)T cells and decreased Tregs.The aforementioned alterations occurred predominantly in the stromal region and were primarily in responders.Non-responders primarily showed decreased Tregs and no increase in CD8^(+)T or dendritic cell infiltration.Furthermore,dendritic cells interacted more closely with CD3^(+)T cells after NACT,an effect primarily observed in responders.RNA-seq data revealed activation of the antigen receptor-mediated signaling pathway and upregulation of major histocompatibility complex(MHC)I and MHC II after chemotherapy,validated using IHC.Conclusions NACT can reduce Tregs,and when tumor cells are effectively killed,antigen presentation is enhanced,subsequently activating antitumor immunity finitely.Our study provides the molecular characteristics and theoretical basis for the simultaneous or sequential combination of platinum-based NACT and immunotherapy for cervical cancer.

Overall survival associated with surgery,radiotherapy,and chemotherapy in metastatic vulvar cancer:A retrospective cohort study based on the SEER database

Background:Large cancer registries help analyze the prognosis of rare malignancies,such as advanced vulvar cancer.This study aimed to compare the overall survival(OS)rates of patients with metastatic vulvar cancer who had undergone chemoradiotherapy and radiotherapy alone and identify prognostic factors using data from the Surveillance,Epidemiology,and End Results(SEER)registry.Methods:In this retrospective cohort study,we used the SEER database to identify patients with metastatic vulvar cancer diagnosed between 2000 and 2019.Propensity score matching was performed to balance the covariates.Kaplan–Meier curves and Cox models were used to analyze OS.Results:A total of 685 patients were included and divided into chemoradiotherapy and radiotherapy groups,and 400 patients were included after propensity score matching.The chemoradiotherapy group had higher OS in the matched cohort(hazard ratio[HR]=0.7367;95%confidence interval[CI]:0.5906–0.9190;P=0.0049)than the radiotherapy group,which was similar to that in the pre-matched cohort(P<0.0001).Patients who had undergone surgery+radiotherapy with or without chemotherapy showed higher OS rates than those who had received radiotherapy with or without chemotherapy for patients aged<75 years and local tumor excision/destruction or surgical removal of the primary site was the recommended surgical choice(P<0.05).Chemoradiotherapy is sufficient for patients 75 years of age.Conclusions:Patients with metastatic vulvar cancer should undergo surgery if they can tolerate it.Adjuvant chemoradiotherapy should be encouraged because this treatment modality was associated with higher OS than radiotherapy alone.