Active immunosurveillance in the tumor microenvironment of colorectal cancer is associated with low frequency tumor budding and improved outcome

Koelzer, Viktor H.; Dawson, Heather; Andersson, Emilia; Karamitopoulou, Eva; Masucci, Giuseppe; Lugli, Alessandro; Zlobec, Inti

doi:10.1016/j.trsl.2015.02.008

Cited by 45 publications

(36 citation statements)

References 35 publications

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“…This suggests that PD-L1 expression by tumor cells is upregulated as a result of a feedback mechanism against activation of host antitumor immunity. In addition, increases in TIA-1 þ TILs have been reported as a favorable prognostic factor in some malignancies, although the activated status of CTLs was not taken into account (39)(40)(41). On the basis of these considerations, the association between high PD-L1 expression and improved prognosis in thymic carcinoma may be explained by high PD-L1 expression following the activation of host antitumor immune responses initiated by infiltrated CTLs.…”

Section: Discussionmentioning

confidence: 99%

Prognostic Value of Programmed Death Ligand 1 and Programmed Death 1 Expression in Thymic Carcinoma

Yokoyama

Miyoshi

Nakashima

et al. 2016

Clinical Cancer Research

115

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Purpose: The immune checkpoint of the programmed death 1/programmed death ligand 1 (PD-1/PD-L1) pathway is believed to play an important role in evasion of host antitumor immune surveillance in various malignancies; however, little is known about its role in thymic carcinoma. This study investigated PD-1/PD-L1 expression and its association with clinicopathologic features, the expression of immune-related proteins in tumor-infiltrating lymphocytes (TIL), and patient prognosis. Experimental Design: PD-L1 and PD-1 expression was evaluated by IHC in 25 thymic carcinoma tissue specimens. Copy number alterations of the PD-L1 gene in 11 cases were assessed in formalin-fixed, paraffin-embedded material using qRT-PCR. Results: Compared with normal subjects, 3 thymic carcinoma patients showed an increase in PD-L1 copy number, whereas 8 did not. PD-L1 was significantly overexpressed in cases with copy number gain as compared with normal cases. High PD-L1 expression was associated with higher disease-free and overall survival rates as compared to cases with low expression. Prognostic analysis revealed low PD-L1 expression and high number of PD-1+ TILs as significant predictors of poor survival, together with Masaoka–Koga stage IVa/IVb disease and incomplete resection. In the quantitative analysis of TILs, PD-L1 expression correlated proportionally with the number of infiltrating CTLs. Conclusions: Here, for the first time, we report that PD-L1 and PD-1 expression might be useful prognostic predictors in thymic carcinoma. Further studies are expected to substantiate the prognostic value of PD-L1 and PD-1 expression, and the potential efficacy of targeting the PD-1/PD-L1 pathway in thymic carcinoma via immunotherapy. Clin Cancer Res; 22(18); 4727–34. ©2016 AACR.

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Section: Discussionmentioning

confidence: 99%

Prognostic Value of Programmed Death Ligand 1 and Programmed Death 1 Expression in Thymic Carcinoma

Yokoyama

Miyoshi

Nakashima

et al. 2016

Clinical Cancer Research

115

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“…Certainly, it is recognised that the immune microenvironment evolves in tandem with stage progression, favouring the development of a more pro-tumour ‘immunome’ as T stage increases (Bindea et al , 2013). As this progresses and anti-tumour immunity is degraded, it may allow the development of further pro-tumour microenvironment characteristics such as recruitment and activation of tumour-associated fibroblasts (Chrysanthopoulou et al , 2014) and budding (Koelzer et al , 2015). …”

Section: Discussionmentioning

confidence: 99%

Tumour invasiveness, the local and systemic environment and the basis of staging systems in colorectal cancer

et al. 2017

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Background:The present study aimed to examine the relationship between tumour invasiveness (T stage), the local and systemic environment and cancer-specific survival (CSS) of patients with primary operable colorectal cancer.Methods:The tumour microenvironment was examined using measures of the inflammatory infiltrate (Klintrup-Makinen (KM) grade and Immunoscore), tumour stroma percentage (TSP) and tumour budding. The systemic inflammatory environment was examined using modified Glasgow Prognostic Score (mGPS) and neutrophil:lymphocyte ratio (NLR). A 5-year CSS was examined.Results:A total of 331 patients were included. Increasing T stage was associated with colonic primary, N stage, poor differentiation, margin involvement and venous invasion (P<0.05). T stage was significantly associated with KM grade (P=0.001), Immunoscore (P=0.016), TSP (P=0.006), tumour budding (P<0.001), and elevated mGPS and NLR (both P<0.05). In patients with T3 cancer, N stage stratified survival from 88 to 64%, whereas Immunoscore and budding stratified survival from 100 to 70% and from 91 to 56%, respectively. The Glasgow Microenvironment Score, a score based on KM grade and TSP, stratified survival from 93 to 58%.Conclusions:Although associated with increasing T stage, local and systemic tumour environment characteristics, and in particular Immunoscore, budding, TSP and mGPS, are stage-independent determinants of survival and may be utilised in the staging of patients with primary operable colorectal cancer.

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“…Aside from impacting the immune contexture of lung cancers, mutant KRAS contributes towards an immune-suppressive microenvironment in CRC, allowing the escape to immune recognition. In CRC, the presence of mutant KRAS is associated with downregulation of major histocompatibility class I (MHCI) molecules [66,67], which means that these cells have an impairment to present antigens ( Figure 2) and are less prone to be detected by the immune system. A clinical trial (ClinicalTrials.gov Identifier: NCT03271047) testing the efficacy of combining the MEK inhibitor binimetinib with anti-PD-1 or anti-CTLA-4 agents (nivolumab/ipilimumab) is currently ongoing for cases of pretreated microsatellite stable metastatic CRC patients that harbor a RAS mutation.…”

Section: Targeting Mutant Kras-driven Effects That Shape the Cancer-imentioning

confidence: 99%

Targeting the Tumor Microenvironment: An Unexplored Strategy for Mutant KRAS Tumors

Carvalho

Machado

Martins

et al. 2019

Cancers

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Current evidence strongly suggests that cancer cells depend on the microenvironment in order to thrive. In fact, signals from the surrounding tumor microenvironment are crucial for cancer cells´aggressiveness, altering their expression profile and favoring their metastatic potential. As such, targeting the tumor microenvironment to impair cancer progression became an attractive therapeutic option. Interestingly, it has been shown that oncogenic KRAS signaling promotes a pro-tumorigenic microenvironment, and the associated crosstalk alters the expression profile of cancer cells. These findings award KRAS a key role in controlling the interactions between cancer cells and the microenvironment, granting cancer a poor prognosis. Given the lack of effective approaches to target KRAS itself or its downstream effectors in the clinic, exploring such interactions may open new perspectives on possible therapeutic strategies to hinder mutant KRAS tumors. This review highlights those communications and their implications for the development of effective therapies or to provide insights regarding response to existing regimens.

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Active immunosurveillance in the tumor microenvironment of colorectal cancer is associated with low frequency tumor budding and improved outcome

Cited by 45 publications

References 35 publications

Prognostic Value of Programmed Death Ligand 1 and Programmed Death 1 Expression in Thymic Carcinoma

Prognostic Value of Programmed Death Ligand 1 and Programmed Death 1 Expression in Thymic Carcinoma

Tumour invasiveness, the local and systemic environment and the basis of staging systems in colorectal cancer

Targeting the Tumor Microenvironment: An Unexplored Strategy for Mutant KRAS Tumors

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