Treatment algorithm and prognostic factors for patients with stage I–III carcinoma of the anal canal: a 20-year multicenter study

Bruyère, Diane; Monnien, Franck; Colpart, Prudence; Roncarati, Patrick; Vuitton, Lucine; Hendrick, Elodie; Lepinoy, A.; Luquain, Alexandra; Pilard, Charlotte; Lerho, Thomas; Molimard, Chloé; Maingon, P.; Arnould́, Laurent; Böne-Lépinoy, M.C.; Dusserre, Laurence; Martin, Laurent; Reynders, Célia; Ancion, Marie; Peiffert, D.; Leroux, Agnès; Hubert, Pascale; Delhorme, Jean-Baptiste; Ghnassia, Jean-Pierre; Woronoff, Anne‐Sophie; Delvenne, Philippe; Prétet, Jean‐Luc; Bosset, Jean-François; Peulen, Olivier; Mougin, Christiane; Valmary‐Degano, Séverine; Herfs, Michaël

doi:10.1038/s41379-020-0637-6

Cited by 19 publications

(18 citation statements)

References 41 publications

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“…This finding is supported by recent data from the US National Cancer Database [25], where using a propensity score matched analysis, HPV status only conferred a significant benefit for overall survival in locally advanced cancers. The independent prognostic role for TIL scores shown here is supported by data from a large Belgian study [26] and supports host lymphocyte recognition in meditating outcomes after CRT. Studies comparing the circulating components of the immune system also support the role of lymphocytes (as opposed to an inflammatory phenotype) in mediating outcomes.…”

Section: Discussionsupporting

confidence: 80%

Multicentre Investigation of Prognostic Factors Incorporating p16 and Tumour Infiltrating Lymphocytes for Anal Cancer After Chemoradiotherapy

et al. 2021

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Aims: Anal squamous cell carcinomas (ASCC) are strongly associated with human papillomaviruses. Standard of care is chemoradiotherapy at uniform doses with no treatment stratification. Immunohistochemical staining for p16INK4A (p16), a surrogate for human papillomaviruses, is prognostic for outcomes. We investigated this alongside clinical-pathological factors, including tumour infiltrating lymphocyte (TIL) scores. Materials and methods: Using an independent, multicentre cohort of 257 ASCC treated with chemoradiotherapy, pretreatment biopsies were stained and scored for p16 and TIL. KaplaneMeier curves were derived for outcomes (disease-free survival [DFS], overall survival and cancer-specific survival), by stage, p16 and TIL scores and Log-rank tests were carried out to investigate prognostic effect. A multivariate analysis was carried out using Cox regression. Results: Stage, sex, p16 and TILs were independently prognostic. Hazard ratios for death (overall survival) were 2.51 (95% confidence interval 1.36e4.63) for p16 negative versus p16 positive, 2.17 (1.34e3.5) for T3/4 versus T1/2, 2.42 (1.52e3.8) for males versus females and 3.30 (1.52e7.14) for TIL1 versus TIL3 (all P < 0.05). Conclusions: We have refined prognostic factors in ASCC. p16 adds to stratification by stage with respect to DFS in early disease and overall survival/DFS in locally advanced cancers. Our data support the role of the host immune response in mediating outcomes. These factors will be prospectively evaluated in PLATO (ISRCTN88455282).

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Section: Discussionsupporting

confidence: 80%

Multicentre Investigation of Prognostic Factors Incorporating p16 and Tumour Infiltrating Lymphocytes for Anal Cancer After Chemoradiotherapy

et al. 2021

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“…PD-L1 expression was considered as positive when membranous immunostaining was detected in ≥1% of cancer cells or inflammatory cells within tumor microenvironment. As previously described, [37][38][39] staining quantification for apoptotic (cleaved caspase 3 + ) cancer cells as well as CD3 + , Foxp3 + , CD68 + , CD206 + and PD-1 + immune cells infiltrating the stroma surrounding tumor cells was performed by computerized counts (QuPath 0.2.0 open source software for digital pathology image analysis). Slides were scanned using 3 dimensional Histech Pannoramic scanner (Sysmex, Villepinte, France).…”

Section: Assessment Of Immunohistochemical Stainingsmentioning

confidence: 99%

Extracellular HMGB1 blockade inhibits tumor growth through profoundly remodeling immune microenvironment and enhances checkpoint inhibitor-based immunotherapy

Hubert

Roncarati

Demoulin

et al. 2021

J Immunother Cancer

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110

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BackgroundHigh-mobility group box 1 (HMGB1) is a multifunctional redox-sensitive protein involved in various intracellular (eg, chromatin remodeling, transcription, autophagy) and extracellular (inflammation, autoimmunity) processes. Regarding its role in cancer development/progression, paradoxical results exist in the literature and it is still unclear whether HMGB1 mainly acts as an oncogene or a tumor suppressor.MethodsHMGB1 expression was first assessed in tissue specimens (n=359) of invasive breast, lung and cervical cancer and the two distinct staining patterns detected (nuclear vs cytoplasmic) were correlated to the secretion profile of malignant cells, patient outcomes and the presence of infiltrating immune cells within tumor microenvironment. Using several orthotopic, syngeneic mouse models of basal-like breast (4T1, 67NR and EpRas) or non-small cell lung (TC-1) cancer, the efficacy of several HMGB1 inhibitors alone and in combination with immune checkpoint blockade antibodies (anti-PD-1/PD-L1) was then investigated. Isolated from retrieved tumors, 14 immune cell (sub)populations as well as the activation status of antigen-presenting cells were extensively analyzed in each condition. Finally, the redox state of HMGB1 in tumor-extruded fluids and the influence of different forms (oxidized, reduced or disulfide) on both dendritic cell (DC) and plasmacytoid DC (pDC) activation were determined.ResultsAssociated with an unfavorable prognosis in human patients, we clearly demonstrated that targeting extracellular HMGB1 elicits a profound remodeling of tumor immune microenvironment for efficient cancer therapy. Indeed, without affecting the global number of (CD45+) immune cells, drastic reductions of monocytic/granulocytic myeloid-derived suppressor cells (MDSC) and regulatory T lymphocytes, a higher M1/M2 ratio of macrophages as well as an increased activation of both DC and pDC were continually observed following HMGB1 inhibition. Moreover, blocking HMGB1 improved the efficacy of anti-PD-1 cancer monoimmunotherapy. We also reported that a significant fraction of HMGB1 encountered within cancer microenvironment (interstitial fluids) is oxidized and, in opposite to its reduced isoform, oxidized HMGB1 acts as a tolerogenic signal in a receptor for advanced glycation endproducts-dependent manner.ConclusionCollectively, we present evidence that extracellular HMGB1 blockade may complement first-generation cancer immunotherapies by remobilizing antitumor immune response.

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“…The protocol was approved by the Ethics Committee of the University Hospital of Liege and the diagnosis of each case was confirmed by experienced histopathologists. IHC analysis was performed using a standard protocol detailed previously [19]. Samples were classified into two groups, namely, EMT-positive vs. EMT-negative, depending on their Vimentin immunoreactivity.…”

Section: Immunohistochemistry and Immunostaining Assessmentmentioning

confidence: 99%

“…Samples were classified into two groups, namely, EMT-positive vs. EMT-negative, depending on their Vimentin immunoreactivity. As previously described [19,20], the IHCs were scored by multiplying two values: intensity (0-3) and extent (0-3), leading to a global score ranging between 0 and 9. Using this latter arbitrary scale, all immunolabelled tissues were evaluated independently by two experienced histopathologists.…”

Section: Immunohistochemistry and Immunostaining Assessmentmentioning

confidence: 99%

The NMD Pathway Regulates GABARAPL1 mRNA during the EMT

et al. 2021

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EMT is a reversible cellular process that is linked to gene expression reprogramming, which allows for epithelial cells to undergo a phenotypic switch to acquire mesenchymal properties. EMT is associated with cancer progression and cancer therapeutic resistance and it is known that, during the EMT, many stress response pathways, such as autophagy and NMD, are dysregulated. Therefore, our goal was to study the regulation of ATG8 family members (GABARAP, GABARAPL1, LC3B) by the NMD and to identify molecular links between these two cellular processes that are involved in tumor development and metastasis formation. IHC experiments, which were conducted in a cohort of patients presenting lung adenocarcinomas, showed high GABARAPL1 and low UPF1 levels in EMT+ tumors. We observed increased levels of GABARAPL1 correlated with decreased levels of NMD factors in A549 cells in vitro. We then confirmed that GABARAPL1 mRNA was indeed targeted by the NMD in a 3′UTR-dependent manner and we identified four overlapping binding sites for UPF1 and eIF4A3 that are potentially involved in the recognition of this transcript by the NMD pathway. Our study suggests that 3′UTR-dependent NMD might be an important mechanism that is involved in the induction of autophagy and could represent a promising target in the development of new anti-cancer therapies.

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Treatment algorithm and prognostic factors for patients with stage I–III carcinoma of the anal canal: a 20-year multicenter study

Cited by 19 publications

References 41 publications

Multicentre Investigation of Prognostic Factors Incorporating p16 and Tumour Infiltrating Lymphocytes for Anal Cancer After Chemoradiotherapy

Multicentre Investigation of Prognostic Factors Incorporating p16 and Tumour Infiltrating Lymphocytes for Anal Cancer After Chemoradiotherapy

Extracellular HMGB1 blockade inhibits tumor growth through profoundly remodeling immune microenvironment and enhances checkpoint inhibitor-based immunotherapy

The NMD Pathway Regulates GABARAPL1 mRNA during the EMT

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