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SERPINB3 (SCCA1) inhibits cathepsin L and lysoptosis, protecting cervical cancer cells from chemoradiation.

ABSTRACT: The endogenous lysosomal cysteine protease inhibitor SERPINB3 (squamous cell carcinoma antigen 1, SCCA1) is elevated in patients with cervical cancer and other malignancies. High serum SERPINB3 is prognostic for recurrence and death following chemoradiation therapy. Cervical cancer cells genetically lacking SERPINB3 are more sensitive to ionizing radiation (IR), suggesting this protease inhibitor plays a role in therapeutic response. Here we demonstrate that SERPINB3-deficient cells have enhanced sensitivity to IR-induced cell death. Knock out of SERPINB3 sensitizes cells to a greater extent than cisplatin, the current standard of care. IR in SERPINB3 deficient cervical carcinoma cells induces predominantly necrotic cell death, with biochemical and cellular features of lysoptosis. Rescue with wild-type SERPINB3 or a reactive site loop mutant indicates that protease inhibitory activity is required to protect cervical tumor cells from radiation-induced death. Transcriptomics analysis of primary cervix tumor samples and genetic knock out demonstrates a role for the lysosomal protease cathepsin L in radiation-induced cell death in SERPINB3 knock-out cells. These data support targeting of SERPINB3 and lysoptosis to treat radioresistant cervical cancers.

SUBMITTER: Wang S

PROVIDER: S-EPMC8755728 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature

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SERPINB3 (SCCA1) inhibits cathepsin L and lysoptosis, protecting cervical cancer cells from chemoradiation.

Wang Songyan S Luke Cliff J CJ Pak Stephen C SC Shi Victoria V Chen Liyun L Moore Jonathan J Andress Arlise P AP Jayachandran Kay K Zhang Jin J Huang Yi Y Platik Marina M Apicelli Anthony A AA Schwarz Julie K JK Grigsby Perry W PW Silverman Gary A GA Markovina Stephanie S

Communications biology 20220112 1

The endogenous lysosomal cysteine protease inhibitor SERPINB3 (squamous cell carcinoma antigen 1, SCCA1) is elevated in patients with cervical cancer and other malignancies. High serum SERPINB3 is prognostic for recurrence and death following chemoradiation therapy. Cervical cancer cells genetically lacking SERPINB3 are more sensitive to ionizing radiation (IR), suggesting this protease inhibitor plays a role in therapeutic response. Here we demonstrate that SERPINB3-deficient cells have enhance ...[more]

PMID: 35022555

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Project description:PurposeCervical cancer remains a leading cause of cancer death in women. While immunotherapy has shown great success in combating cancer, the value of immunotherapy in cervical cancer is still only beginning to be explored. Thus, we performed a prospective analysis of patient blood and tumor samples at the beginning and end of conventional chemoradiation to assess changes in the immune cell and immunoreceptor compartments, and investigate if and when the addition of immunotherapy could be beneficial.MethodsPatients with FIGO II-III cervical cancer receiving standard chemoradiation between January 2020 and December 2021 were included. We collected tumor and blood samples from patients before and at the end of therapy and analyzed immune cell composition and immune checkpoint receptor expression on both immune and tumor cells using multicolor flow cytometry.ResultsIn all, 34 patients were eligible in the study period; 22 could be included and analyzed in this study. We found that chemoradiation significantly reduces T cell numbers in both tumors and blood, but increases macrophage and neutrophil numbers in tumors. Furthermore, we found that the percentage of immune checkpoint receptor PD‑1 and TIGIT-expressing cells in tumors was significantly reduced at the end of therapy and that CD4 and CD8 memory T cell populations were altered by chemoradiation. In addition, we observed that while PD-L1 expression intensity was upregulated by chemoradiation on blood CD8 cells, PD-L1 expression frequency and the expression intensity of antigen-presenting molecule MHC‑I were significantly reduced on tumor cells.ConclusionOur data demonstrate that chemoradiation significantly alters the immune cell composition of human cervical tumors and the expression of immune checkpoint receptors on both lymphocytes and tumor cells. As our results reveal that the percentage of PD‑1+ CD8 cells in the tumor as well as the frequency of PD-L1-expressing tumor cells were reduced at the end of therapy, neoadjuvant or simultaneous anti-PD‑1 or anti-PD-L1 treatment might provide better treatment efficiency in upcoming clinical studies.

Dataset Information

SERPINB3 (SCCA1) inhibits cathepsin L and lysoptosis, protecting cervical cancer cells from chemoradiation.

Publications

SERPINB3 (SCCA1) inhibits cathepsin L and lysoptosis, protecting cervical cancer cells from chemoradiation.

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