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Chemoradiotherapy-induced ACKR2+ tumor cells drive CD8+ T cell senescence and tumor recurrence

ABSTRACT: T cell senescence is a dysfunctional state distinct from exhaustion, yet the mechanism driving CD8+ T cell senescence directly in tumor microenvironment and its impact on cancer prognosis remain elusive. Here, by using single cell RNA sequencing of human cervical cancer tissues, we found that concurrent chemoradiotherapy (CCRT) specifically promoted CD8+ T cell senescence, which is driven by a subpopulation of ACKR2+ CCRT-resistance tumor cells. Mechanistically, in response to CCRT treatment, ACKR2 was directly induced and could also be upregulated through its ligands CC chemokines that produced by activated myeloid and T cells. Subsequently, these ACKR2+ tumor cell subpopulation also produced TGFβ to drive CD8+ T cell senescence, thereby compromising antitumor immunity. Moreover, retrospective analysis showed that ACKR2 level and CD8+ T cell senescence was greatly enhanced in cervical cancer patients who recurred after CCRT, thereby predicting poor prognosis in these patients. Overall, we identified a subpopulation of CCRT-resistant ACKR2+ tumor cells in driving CD8+ T cell senescence and thus tumor recurrence, which may represent a critical mechanism in mediating CCRT resistance, and highlighted the therapeutic potential of targeting ACKR2 or CD8+ T cell senescence in the treatment of CCRT-resistant cancer patients.

ORGANISM(S): Homo sapiens

PROVIDER: GSE236738 | GEO | 2024/06/07

REPOSITORIES: GEO

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Project description:Purpose: We aimed to investigate the distinct transcriptional landscape in the poor responders to concurrent chemoradiotherapy (CCRT) and to gain mechanistic insights on treatment resistance in cervical cancer. Methods: RNA sequencing was performed using archived pre-treatment tissue biopsies of patients with locally advanced cervical cancer treated with concurrent platinum-based CCRT. Transcriptome data of patients with no durable benefit (NDB; progression-free period < 3 years) and durable clinical benefit (DCB; progression-free period > 5 years) after were compared. NDB score was estimated for each patient using the differentially expressed genes between NDB and DCB patients. Three independent cohorts, including The Cancer Genome Atlas cervical cancer (TCGA-CESC) cohort, were utilized for validation of NDB score. Potential response to PD-1 blockade was estimated with Tumor Immune Dysfunction and Exclusion (TIDE) score and T-cell-inflamed gene expression profile (GEP). Results: Patients with NDB exhibited a distinct transcriptional profile compared to those with DCB such as higher signatures of extracellular matrix organization and epithelial-to-mesenchymal transition. The fraction of cancer-associated fibroblasts (CAFs) within the tumor was significantly higher in NDB than DCB patients. Higher NDB score was significantly associated with poor survival in the TCGA-CESC cohort (n = 274; P = 0.015), but only in patients that received curative aim radiotherapy (P = 0.002) and not in patients who received other treatments (P = 0.57). The transcriptomic characteristics of patients with NDB were recapitulated in patients with high NDB score in TCGA-CESC. Patients with high NDB score displayed significantly higher TIDE prediction score and lower T-cell-inflamed GEP score compared to patients with low NDB scores. Conclusion: Cervical cancer patients with poor treatment outcome following CCRT exhibited a distinct gene signature that was able to predict treatment outcomes. For poor responders, immune checkpoint inhibitors may be less effective and CAF-targeting treatments may be a promising approach.

Project description:The cellular heterogeneity of one patient derived orthotopic breast cancer xenograft model (PDBCX) was investigated using flow cytometry , combined with assessment of in vivo tumorigenicity and whole genome expression profiling. Epithelial cell adhesion molecule (EpCAM) was revealed as a highly specific cell surface marker of the human tumor cell population in both xenografts. Based on expression patterns observed in primary tumor tissue, SSEA-4 and CD24 were chosen as markers to further subdivide the luminal tumor cells into four subpopulations. FACS sorting was used to isolate four cell subpopulations. Results: In vivo tumorigenicity assay showed that SSEA-4+/CD24+ cells were non-tumorigenic, while the three other subpopulations were tumorigenic. Tumors resulting from the SSEA-4+/CD24- subpopulation of luminal cancer cells, did not express CD24, while tumors arising from the SSEA-4-/CD24-, and SSEA-4-/CD24+ populations both recapitulated the original tumor containing all four subpopulations. Whole genome expression analysis revealed distinct transcriptional profiles, and 44 genes were significantly differentially expressed when comparing the tumorigenic vs non-tumorigenic populations. Several interesting genes putatively suppressing the cancer cells ability to initiate tumors in vivo were upregulated in the non-tumorigenic population. We here show that tumor initiating cells within one primary tumor evidently included more than one phenotype. Furthermore, with respect to cell surface marker expression, one of the subpopulations produced tumors unlike both the originating cells, and the original tumor. Discussion: Our results imply that subpopulations from one primary tumor can give rise to dissimilar daughter tumors. These tumors may not necessarily respond to the same targeted treatment, and thereby represent a therapy escape mechanism. This study highlights that to remove the risk of breast cancer recurrence, inhibition of the molecules critical for driving the tumor progression in several tumor cell subpopulations might be essential Gene expression was measured in four cell subpopulations isolated from Patient derived human luminal-like breast cancer xenograft. Four replicates from three subpopulations and three replicates from one subpopulation.

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Chemoradiotherapy-induced ACKR2+ tumor cells drive CD8+ T cell senescence and tumor recurrence

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