Tumour budding in solid cancers Lugli, Alessandro; Zlobec, Inti; Berger, Martin D ...
Nature reviews. Clinical oncology,
02/2021, Letnik:
18, Številka:
2
Journal Article
Recenzirano
Tumour budding is an emerging prognostic biomarker in colorectal cancer (CRC) and other solid cancers. Tumour buds are usually defined as isolated single cancer cells or clusters of up to four cancer ...cells located at the invasive tumour front. The prognostic value of tumour budding is now supported by a large body of evidence, whereas the utility of this phenotype as a predictive biomarker remains under investigation. The application of tumour budding indices in clinical practice requires a standardized scoring system that can be tailored to specific tumour types and clinical scenarios. In the context of CRC, tumour budding can be assessed according to the method agreed at the International Tumour Budding Consensus Conference (ITBCC) in 2016. Using the ITBCC scoring system, tumour budding is an independent predictor of lymph node metastasis in patients with pT1 CRC and of unfavourable survival in patients with stage II colon cancer. Regardless of the clinical scenario or tumour type, the assertion that 'the more tumour buds, the worse the clinical outcome' applies. In this Review, we provide an overview of tumour budding in solid cancers, highlighting the molecular and biological aspects of this phenomenon, including its associations with epithelial-mesenchymal transition and features of the tumour microenvironment. We also describe the available evidence demonstrating the value of tumour budding as a biomarker across various solid cancers.
•Chemokines induce chemotaxis, promote differentiation of immune cells, and cause tissue extravasation.•The CXCL9, -10, -11/CXCR3 axis regulates immune cell migration, differentiation, and activation ...through paracrine axis.•The axis induces tumor growth and metastasis through autocrine axis.•Preclinical researches are defining the axis as a promising target for cancer treatment.•Other immune consistent pathways strongly crosslink with this axis.
Chemokines are proteins which induce chemotaxis, promote differentiation of immune cells, and cause tissue extravasation. Given these properties, their role in anti-tumor immune response in the cancer environment is of great interest. Although immunotherapy has shown clinical benefit for some cancer patients, other patients do not respond. One of the mechanisms of resistance to checkpoint inhibitors may be chemokine signaling. The CXCL9, -10, -11/CXCR3 axis regulates immune cell migration, differentiation, and activation, leading to tumor suppression (paracrine axis). However, there are some reports that show involvements of this axis in tumor growth and metastasis (autocrine axis). Thus, a better understanding of CXCL9, -10, -11/CXCR3 axis is necessary to develop effective cancer control. In this article, we summarize recent evidence regarding CXCL9, CXCL10, CXCL11/CXCR3 axis in the immune system and discuss their potential role in cancer treatment.
•B cells secrete immunoglobulins, promote T cell response, kill cancer cells directly.•B cell and B cell-related pathways play key roles in activating local immune response.•In humoral immunity, B ...cell and B cell-related pathways play the important roles.•Recent evidences show the potential role of B cell for novel cancer treatment.
B cells are recognized as the main effector cells of humoral immunity which suppress tumor progression by secreting immunoglobulins, promoting T cell response, and killing cancer cells directly. Given these properties, their anti-tumor immune response in the tumor micro-environment (TME) is of great interest. Although T cell-related immune responses have become a therapeutic target with the introduction of immune checkpoint inhibitors, not all patients benefit from these treatments. B cell and B cell-related pathways (CCL19, −21/CCR7 axis and CXCL13/CXCR5 axis) play key roles in activating immune response through humoral immunity and local immune activation via tertiary lymphoid structure (TLS) formation. However they have some protumorigenic works in the TME. Thus, a better understanding of B cell and B cell-related pathways is necessary to develop effective cancer control. In this review, we summarize recent evidences regarding the roles of B cell and B cell-related pathways in the TME and immune response and discuss their potential roles for novel cancer treatment strategies.
•Approximately 10% of all gastric cancers are related to EBV infection.•EBV associated gastric cancers have a distinct molecular and clinical profile.•These tumors have higher PD-L1 expression, ...PIK3CA mutations and hypermethylation.•The role of immunotherapy in EBV associated gastric cancer is under investigation.•EBV is a promising biomarker in gastric cancer.
Epstein-Barr virus associated gastric cancer (EBVaGC) comprises approximately 10% of gastric carcinomas. Multiple factors contribute to tumorigenesis, including EBV driven hypermethylation of tumor suppressor genes, inflammatory changes in gastric mucosa, host immune evasion by EBV and changes in cell cycle pathways. The unique molecular characteristics of EBVaGC, such as programmed death ligand 1 (PD-L1) overexpression, highlight the potential for using EBV as a biomarker for response to immunotherapy. Few studies have reported benefit from immunotherapy in EBV positive cancers, and clinical trials investigating the impact of checkpoint inhibitors in EBVaGC are currently underway. This review provides the most recent updates on molecular pathophysiology, epidemiology, clinical features and treatment advances pertaining to EBVaGC.
Tumour budding in colorectal cancer has become an important prognostic factor. Represented by single cells or small tumour cell clusters at the invasion front of the tumour mass, these tumour buds ...seem to reflect cells in a 'hybrid' state of epithelial-mesenchymal transition, and evidence indicates that the presence of these entities is associated with lymph node metastasis, local recurrence and distant metastatic disease. The International Tumour Budding Consensus Conference (ITBCC) has highlighted a scoring system for the reporting of tumour budding in colorectal cancer, as well as different clinical scenarios that could affect patient management. Other organs are not spared: tumour budding has been described in numerous gastrointestinal and non-gastrointestinal cancers. Here, we give an update on ITBCC validation studies in the context of colorectal cancer and the clinical implications of tumour budding throughout the upper gastrointestinal and pancreatico-biliary tract.
Colorectal cancer (CRC) is the third most frequent cancer worldwide, and its incidence is steadily increasing. During the last two decades, a tremendous improvement in outcome has been achieved, ...mainly due to the introduction of novel drugs, targeted treatment, immune checkpoint inhibitors (CPIs) and biomarker-driven patient selection. Moreover, progress in molecular diagnostics but also improvement in surgical techniques and local ablative treatments significantly contributed to this success. However, novel therapeutic approaches are needed to further improve outcome in patients diagnosed with metastatic CRC. Besides the established biomarkers for mCRC, such as microsatellite instability (MSI) or mismatch repair deficiency (dMMR), RAS/BRAF, sidedness and HER2 amplification, new biomarkers have to be identified to better select patients who derive the most benefit from a specific treatment. In this review, we provide an overview about therapeutic relevant and established biomarkers but also shed light on potential promising markers that may help us to better tailor therapy to the individual mCRC patient in the near future.
Tumor budding is a robust prognostic parameter in colorectal cancer and can be used as an additional factor to guide patient management. Although backed by large bodies of data, a standardized ...scoring method is essential for integrating tumor budding in reporting protocols. The International Tumor Budding Consensus Conference (ITBCC) 2016 has proposed such a scoring system. The aim of this study is to validate the ITBCC method of tumor budding assessment on a well-characterized colorectal cancer cohort. Three hundred seventy-nine patients with resected stage I-IV colorectal cancer were entered into the study. Tumor budding was scored by 2 pathologists according to the ITBCC recommendations on hematoxylin and eosin–stained slides and scored as BD1 (low grade), BD2 (intermediate grade), and BD3 (high grade). Analysis was performed using a 3-tier approach, a 2-tier approach (BD1 + 2 versus BD3) and budding as a continuous variable. High-grade tumor budding was associated with adverse clinicopathological features including higher pT, higher pN stage, and higher TNM stage (all P < .001) and poorer overall survival on univariate analysis (P = .0251 for BD1/2/3, P = .0106 for BD1 + 2 versus BD3, and P = .0195 for continuous scores; hazard ratio, 1.023 95% confidence interval, 1.004-1.043 per bud). In stage II cancers, BD3 was associated with poorer disease-free survival (P < .01). Tumor budding assessed by the method proposed by the ITBCC is applicable to colorectal cancer resection specimens and can be used for widespread reporting in routine.
•The ITBCC 2016 has initiated the inclusion of tumor budding in CRC reporting protocols.•Validation studies provide further ground to implement the ITBCC scoring system in routine.•ITBCC tumor budding is recommended as an additional prognostic factor in CRC.
The estimation of risk of recurrence for patients with colon carcinoma must be improved. A robust immune score quantification is needed to introduce immune parameters into cancer classification. The ...aim of the study was to assess the prognostic value of total tumour-infiltrating T-cell counts and cytotoxic tumour-infiltrating T-cells counts with the consensus Immunoscore assay in patients with stage I–III colon cancer.
An international consortium of 14 centres in 13 countries, led by the Society for Immunotherapy of Cancer, assessed the Immunoscore assay in patients with TNM stage I–III colon cancer. Patients were randomly assigned to a training set, an internal validation set, or an external validation set. Paraffin sections of the colon tumour and invasive margin from each patient were processed by immunohistochemistry, and the densities of CD3+ and cytotoxic CD8+ T cells in the tumour and in the invasive margin were quantified by digital pathology. An Immunoscore for each patient was derived from the mean of four density percentiles. The primary endpoint was to evaluate the prognostic value of the Immunoscore for time to recurrence, defined as time from surgery to disease recurrence. Stratified multivariable Cox models were used to assess the associations between Immunoscore and outcomes, adjusting for potential confounders. Harrell's C-statistics was used to assess model performance.
Tissue samples from 3539 patients were processed, and samples from 2681 patients were included in the analyses after quality controls (700 patients in the training set, 636 patients in the internal validation set, and 1345 patients in the external validation set). The Immunoscore assay showed a high level of reproducibility between observers and centres (r=0·97 for colon tumour; r=0·97 for invasive margin; p<0·0001). In the training set, patients with a high Immunoscore had the lowest risk of recurrence at 5 years (14 8% patients with a high Immunoscore vs 65 (19%) patients with an intermediate Immunoscore vs 51 (32%) patients with a low Immunoscore; hazard ratio HR for high vs low Immunoscore 0·20, 95% CI 0·10–0·38; p<0·0001). The findings were confirmed in the two validation sets (n=1981). In the stratified Cox multivariable analysis, the Immunoscore association with time to recurrence was independent of patient age, sex, T stage, N stage, microsatellite instability, and existing prognostic factors (p<0·0001). Of 1434 patients with stage II cancer, the difference in risk of recurrence at 5 years was significant (HR for high vs low Immunoscore 0·33, 95% CI 0·21–0·52; p<0·0001), including in Cox multivariable analysis (p<0·0001). Immunoscore had the highest relative contribution to the risk of all clinical parameters, including the American Joint Committee on Cancer and Union for International Cancer Control TNM classification system.
The Immunoscore provides a reliable estimate of the risk of recurrence in patients with colon cancer. These results support the implementation of the consensus Immunoscore as a new component of a TNM-Immune classification of cancer.
French National Institute of Health and Medical Research, the LabEx Immuno-oncology, the Transcan ERAnet Immunoscore European project, Association pour la Recherche contre le Cancer, CARPEM, AP-HP, Institut National du Cancer, Italian Association for Cancer Research, national grants and the Society for Immunotherapy of Cancer.
The flare of radiation from the tidal disruption and accretion of a star can be used as a marker for supermassive black holes that otherwise lie dormant and undetected in the centres of distant ...galaxies. Previous candidate flares have had declining light curves in good agreement with expectations, but with poor constraints on the time of disruption and the type of star disrupted, because the rising emission was not observed. Recently, two 'relativistic' candidate tidal disruption events were discovered, each of whose extreme X-ray luminosity and synchrotron radio emission were interpreted as the onset of emission from a relativistic jet. Here we report a luminous ultraviolet-optical flare from the nuclear region of an inactive galaxy at a redshift of 0.1696. The observed continuum is cooler than expected for a simple accreting debris disk, but the well-sampled rise and decay of the light curve follow the predicted mass accretion rate and can be modelled to determine the time of disruption to an accuracy of two days. The black hole has a mass of about two million solar masses, modulo a factor dependent on the mass and radius of the star disrupted. On the basis of the spectroscopic signature of ionized helium from the unbound debris, we determine that the disrupted star was a helium-rich stellar core.
Aims
Epstein–Barr virus (EBV) in‐situ hybridisation and mismatch repair (MMR) protein immunohistochemistry identifies two subgroups of gastric cancer (GC) with high immunogenicity and likelihood for ...response to immune check‐point inhibition. As tumour biology may change during the metastatic course, which can negatively influence the success of therapeutic decisions made on primary tissue, we investigated the consistency of GC EBV and MMR status within primary tumours and metastases.
Methods and results
We investigated a cohort of 415 primary resected GC, including 111 cases with corresponding distant metastases and 297 cases with lymph node metastases. Tumours were analysed by EBV in‐situ hybridisation and MLH1, PMS2, MSH2 and MSH6 immunohistochemistry using tissue microarray technique. Primary tumours were grouped as EBV‐positive MMR‐proficient, EBV‐negative MMR‐deficient and EBV‐negative MMR‐proficient. Eleven of 415 (2.7%) of primary tumours were EBV‐positive MMR‐proficient, whereas 49 of 415 (11.8%) of tumours were EBV‐negative MMR‐deficient. EBV and MMR protein status showed full concordance with that of the primary tumours. MMR‐deficient tumours were of lower pT‐category (P < 0.001), had fewer lymph node metastases 24 of 49 (49%) versus 273 of 361 (75.6%) cases; P < 0.001 and a lower rate of distant metastases six of 49 (12.2%) versus 105 of 366 (28.7%) cases; P = 0.015.
Conclusion
We demonstrate a strong correlation of EBV and MMR status between primary tumours, lymph node and distant metastases in a large series of primary resected GC. The cases showed the expected frequency of EBV‐positive MMR‐deficient and EBV‐negative MMR‐proficient tumours. We conclude that tissue testing for molecular subtyping for therapeutic decision‐making can be reliably performed on primary tumours and metastases in GC.
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