Most (if not all) tumors emerge and progress under a strong evolutionary pressure imposed by trophic, metabolic, immunological, and therapeutic factors The relative impact of these factors on tumor evolution changes over space and time, ultimately favoring the establishment of a neoplastic microenvironment that exhibits considerable genetic, phenotypic, and behavioral heterogeneity in all its components Here, we discuss the main sources of intratumoral heterogeneity and its impact on the natural history of the disease, including sensitivity to treatment, as we delineate potential strategies to target such a detrimental feature of aggressive malignancies The many levels of heterogeneity within tumors dictate their response to therapy and should be considered in future therapeutic regimes

Intratumoral heterogeneity in cancer progression and response to immunotherapy.

Background Solute carrier family 7 member 11(SLC7A11) is a component of cysteine/glutamate transporter, which plays a key role in tumor growth; however, its underlying effect on radiosensitivity in esophageal squamous cell carcinoma (ESCC) remains unclear. This study aimed to clarify SLC7A11's expression and correlation with nuclear expression of nuclear factor erythroid-2 (NRF2)-associated radioresistance in ESCC. Methods We included 127 ESCC patients who received radical chemoradiotherapy. Immunohistochemical staining was used to detect SLC7A11 and NRF2 nuclear expression, and the relationship between clinicopathological characteristics and survival rates or therapy response were evaluated. Western blot, dual-reporter assays and Chromatin immunoprecipitation (ChIP)-sequencing were used to analyze their relationship in vitro. Their roles in radioresistance were then investigated through multiple validation steps. Results NRF2 nuclear expression and SLC7A11 expression were overexpressed in ESCC tissues and were positively correlated with one another. NRF2 nuclear expression was significantly associated with tumor length, lymph node metastasis, and TNM stage, while SLC7A11 expression was associated with lymph node metastasis. Patients with high NRF2 nuclear expression and SLC7A11 expression had significantly shorter overall and progression-free survival, and poor treatment response. The multivariate model showed that NRF2 nuclear expression and SLC7A11 expression, sex and tumor location are independent prognostic factors. In vitro analysis confirmed that hyperactivation of NRF2 induced SLC7A11 expression by directly binding to its promoter region, promoting radioresistance, reducing radiotherapy-induced lipid peroxidation levels, PTGS2 expression, and radiotherapy-related ferroptosis morphologic features. Conclusion Our study reveals a connection between high SLC7A11 expression and NRF2 nuclear expression in patients with ESCC that was related to worse survival and poorer therapy outcomes. SLC7A11-mediated ferroptosis inhibition induced NRF2-associated radioresistance, highlighting potential of NRF2/SLC7A11/ferroptosis axis as future therapeutic targets against therapy resistance biomarker.

/pdf/slc7a11-regulated-by-nrf2-modulates-esophageal-squamous-cell-2ihv36fpan.pdf

SLC7A11 regulated by NRF2 modulates esophageal squamous cell carcinoma radiosensitivity by inhibiting ferroptosis

Tislelizumab combined with chemotherapy as neoadjuvant therapy for surgically resectable esophageal cancer: A prospective, single-arm, phase II study (TD-NICE).

Patients with esophageal cancer are confronted with high mortality rates. Whether it is esophageal squamous cell carcinoma (ESCC) or esophageal adenocarcinoma (EAC), patients usually present at advanced stages, with treatment options traditionally involving chemotherapy in metastatic settings. With the comprehensive genomic characterization of esophageal cancers, targeted therapies are gaining interest and agents such as ramucirumab, trastuzumab and pembrolizumab are already being used for the treatment of EAC. Pembrolizumab has recently been FDA-approved for PD-L1 positive, locally advanced or metastatic ESCC. Despite comprehensive molecular characterization, however, available targed therapies for ESCC are still lagging behind. Herein, we discuss current trends towards more targeted therapies in esophageal cancers, taking into consideration unique features of ESCCs and EACs. Patients progressing on standard therapies should be subjected to genomic profiling and considered for clinical trials aimed at testing targeted therapies. Future targeted therapies may include CDK4/6 inhibitors, PARP inhibitors and inhibitors targeting the NRF2 and Wnt signaling pathways. Ultimately, optimized biomarker assays and next generation sequencing platforms may allow for the identification of subcategories of ESCC and EAC patients that will benefit from selective targeted therapies and/or combinations thereof.

Esophageal carcinoma: Towards targeted therapies.

Abstract During the course of tumorigenesis and subsequent metastasis, malignant cells gradually diversify and become more heterogeneous. Consequently, the tumor mass might be infiltrated by diverse immune-related components, including the cytokine/chemokine environment, cytotoxic activity, or immunosuppressive elements. This immunological heterogeneity is universally presented spatially or varies temporally along with tumor evolution or therapeutic intervention across almost all solid tumors. The heterogeneity of anti-tumor immunity shows a profound association with the progression of disease and responsiveness to treatment, particularly in the realm of immunotherapy. Therefore, an accurate understanding of tumor immunological heterogeneity is essential for the development of effective therapies. Facilitated by multi-regional and -omics sequencing, single cell sequencing, and longitudinal liquid biopsy approaches, recent studies have demonstrated the potential to investigate the complexity of immunological heterogeneity of the tumors and its clinical relevance in immunotherapy. Here, we aimed to review the mechanism underlying the heterogeneity of the immune microenvironment. We also explored how clinical assessments of tumor heterogeneity might facilitate the development of more effective personalized therapies. 

https://ehoonline.biomedcentral.com/counter/pdf/10.1186/s40164-022-00277-y

Heterogeneity of the tumor immune microenvironment and its clinical relevance

Esophageal squamous cell carcinoma (ESCC) is a poor-prognosis cancer type with limited understanding of its molecular etiology. Using 508 ESCC genomes, we identified five novel significantly mutated genes and uncovered mutational signature clusters associated with metastasis and patients’ outcomes. Several functional assays implicated that NFE2L2 may act as a tumor suppressor in ESCC and that mutations in NFE2L2 probably impaired its tumor-suppressive function, or even conferred oncogenic activities. Additionally, we found that the NFE2L2 mutations were significantly associated with worse prognosis of ESCC. We also identified potential noncoding driver mutations including hotspot mutations in the promoter region of SLC35E2 that were correlated with worse survival. Approximately 5.9% and 15.2% of patients had high tumor mutation burden or actionable mutations, respectively, and may benefit from immunotherapy or targeted therapies. We found clinically relevant coding and noncoding genomic alterations and revealed three major subtypes that robustly predicted patients’ outcomes. Collectively, we report the largest dataset of genomic profiling of ESCC useful for developing ESCC-specific biomarkers for diagnosis and treatment.

Whole-genome sequencing of 508 patients identifies key molecular features associated with poor prognosis in esophageal squamous cell carcinoma.

Esophageal squamous cell carcinoma (ESCC) ranks fourth among cancer-related deaths in China due to the lack of actionable molecules. We performed whole-exome and T-cell receptor (TCR) repertoire sequencing on multi-regional tumors, normal tissues and blood samples from 39 ESCC patients. The data revealed 12.8% of ERBB4 mutations at patient level and functional study supported its oncogenic role. 18% of patients with early BRCA1/2 variants were associated with high-level contribution of signature 3, which was validated in an independent large cohort (n = 508). Furthermore, knockdown of BRCA1/2 dramatically increased sensitivity to cisplatin in ESCC cells. 5% of patients harbored focal high-level amplification of CD274 that led to massive expression of PD-L1, and might be more sensitive to immune checkpoint blockade. Finally, we found a tight correlation between genomic and TCR repertoire intra-tumor heterogeneity (ITH). Collectively, we reveal high-level ITH in ESCC, identify several potential actionable targets and may provide novel insight into ESCC treatment. Esophageal squamous cell carcinoma (ESCC) is highly prevalent in China. Here, the authors carry out multi-region sampling of Chinese ESCC samples, and find recurrent ERBB4 mutations, BRCA1/2 variants, and amplification of CD274; together with high levels of genomic and T-cell receptor heterogeneity.

/pdf/multi-region-sequencing-unveils-novel-actionable-targets-and-v3g2xz6bif.pdf

Multi-region sequencing unveils novel actionable targets and spatial heterogeneity in esophageal squamous cell carcinoma

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Whole-genome sequencing of 508 patients identifies key molecular features associated with poor prognosis in esophageal squamous cell carcinoma.

Multi-region sequencing unveils novel actionable targets and spatial heterogeneity in esophageal squamous cell carcinoma