The Balance Between Cytotoxic T-cell Lymphocytes and Immune Checkpoint Expression in the Prognosis of Colon Tumors

Marisa, Laëtitia; Svrcek, Magali; Collura, Ada; Becht, Étienne; Cervera, Pascale; Wanherdrick, Kristell; Buhard, Olivier; Goloudina, Anastasia R.; Jonchère, Vincent; Sèlves, Janick; Milano, Gérard; Guénot, Dominique; Cohen, Romain; Colas, Chrystelle; Laurent‐Puig, Pierre; Olschwang, Sylviane; Lefèvre, Jérémie H.; Parc, Yann; Boige, Valérie; Lepage, Côme; André, Thierry; Fléjou, Jean‐François; Dérangère, Valentin; Ghiringhelli, François; Reyniès, Aurélien de; Duval, Alex

doi:10.1093/jnci/djx136

Cited by 98 publications

(76 citation statements)

References 31 publications

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“…Thus, our results are in line with and extend those of Galon et al who clearly demonstrated that a subgroup of MSS CRC exhibits a high Th1/Tc1/IFNγ gene signature, as the majority of MSI CRC. 11,18,38 Moreover, we recapture the favorable prognostic impact of this Th1/Tc1/ IFNγ gene signature in MSI as well as in MSS CRC by quantifying the density of Tbet+ TILs. The identification of Tbet+ TILs by immunohistochemistry was previously reported in CRC in only few studies, with a higher density in MSI than in MSS CRC in line with our results.…”

Section: Discussionmentioning

confidence: 99%

The density of Tbet+ tumor-infiltrating T lymphocytes reflects an effective and druggable preexisting adaptive antitumor immune response in colorectal cancer, irrespective of the microsatellite status

et al. 2019

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Purpose: The recent success of anti-PD1 antibody in metastatic colorectal cancer (CRC) patients with microsatellite instability (MSI), known to be associated with an upregulated Th1/Tc1 gene signature, provides new promising therapeutic strategies. However, the partial objective response highlights a crucial need for relevant, easily evaluable, predictive biomarkers. Here we explore whether in situ assessment of Tbet+ tumor infiltrating lymphocytes (TILs) reflects a pre-existing functional antitumor Th1/Tc1/IFNγ response, in relation with clinicopathological features, microsatellite status and expression of immunoregulatory molecules (PD1, PDL1, IDO-1). Methodology: In two independent cohorts of CRC (retrospective n = 80; prospective n = 27) we assessed TILs density (CD3, Tbet, PD1) and expression profile of PDL1 and IDO-1 by immunohistochemistry/image analysis. Furthermore, the prospective cohort allowed to perform ex vivo CRC explant cultures and measure by Elisa the IFNγ response, at baseline and upon anti-PD1 treatment. Results: The density of Tbet+ TILs was significantly higher in MSI CRC, especially in the medullary subtype but also in a subgroup of MSS (microsatellite stable), and positively correlated with PD1 and PDL1 expression, but not with IDO-1. Finally, a high number of Tbet+ TILs was associated with a favorable overall survival. These Tbet+ TILs were functional as their density positively correlated with basal IFNγ levels. In addition, the combined score of Tbet+ PD1+ TILs coupled with IDO-1 expression predicted the magnitude of the IFNγ response upon anti-PD1. Conclusion: Altogether, immunohistochemical quantification of Tbet+ TILs is a reliable and accurate tool to recapitulate a preexisting Th1/Tc1/IFNγ antitumor response that can be reinvigorated by anti-PD1 treatment.

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Section: Discussionmentioning

confidence: 99%

The density of Tbet+ tumor-infiltrating T lymphocytes reflects an effective and druggable preexisting adaptive antitumor immune response in colorectal cancer, irrespective of the microsatellite status

et al. 2019

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“…Another study showed the lymphocyte infiltration response to the tumour. Increased lymphocytic reactions have been associated with a better outcome [18]. In addition, platelets could secrete cellular growth factors such as platelet-derived growth factor, vascular endothelial growth factor, transforming growth factor β, and platelet factor 4, followed by the stimulation of tumour angiogenesis and growth [19,20].…”

Section: Discussionmentioning

confidence: 99%

Perioperative changes of inflammation-based biomarker for predicting the prognosis in colorectal cancer patients: a retrospective analysis

Wang

Yan

et al. 2019

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Introduction: Perioperative inflammatory markers, including the neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR), are associated with oncological prognosis. However, their changes in colorectal cancer surgery for predicting the prognosis are rarely investigated. Aim: To compare perioperative changes to evaluate the prognostic significance of patients' survival. Material and methods: Retrospective clinical data and baseline laboratory parameters of 183 colorectal cancer (CRC) patients who underwent curative surgery were collected between January 2007 and January 2013. The clinicopathological characteristics were compared. Statistical analysis was used to identify the predictive changes of perioperative NLR and PLR associated with survival prognosis. Results: ROC analysis indicated that perioperative NLR/PLR showed higher predictive accuracy for prognosis, and the optimal cutoff values of pre-NLR, post-NLR, pre-PLR, and post-PLR were 2.94, 4.32, 184.29, and 212.37, respectively. Kaplan-Meier analysis suggested that the four groups stratified by perioperative changes had significantly different recurrence-free survival and overall survival (p < 0.05). Univariate and multivariable analysis revealed that patients with higher cancer stage, lymph node metastasis, and perioperative change of NLR/PLR (HH, LH) had significant association with poor prognosis of RFS and OS (all p < 0.05). Conclusions: Perioperative NLR and PLR might be good predictors for prognosis in CRC patients who have undergone curative surgery, which could guide the customised therapeutic strategy. Furthermore, their assessment could contribute to accurately predicting oncologic outcomes and provide an in-depth understanding of the patients, which could guide the operational strategy.

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“…On one hand, CTLs recognize tumor cells through tumor-specific antigens to mount an antitumor immune response and suppress tumor progression. However, tumor cells often mount a counterattack by multiple mechanisms including loss of antigen expression, and both primary and acquired resistance mechanisms, which in turn shut down the tumor-reactive CTLs in the tumor microenvironment (13)(14)(15)(16). Therefore, tumor cells hijack the corepressive receptor-based immune checkpoint mechanism to suppress tumor-reactive CTLs to avoid immune rejection (17)(18)(19)(20).…”

Section: Introductionmentioning

confidence: 99%

An osteopontin/CD44 immune checkpoint controls CD8+ T cell activation and tumor immune evasion

Klement¹,

Paschall²,

Redd³

et al. 2018

Journal of Clinical Investigation

229

175

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The Balance Between Cytotoxic T-cell Lymphocytes and Immune Checkpoint Expression in the Prognosis of Colon Tumors

Abstract: ICK expression cancels the prognostic relevance of CTLs in highly immunogenic colon tumors and predicts a poor outcome in MSI CRC patients.

Cited by 98 publications

References 31 publications

The density of Tbet+ tumor-infiltrating T lymphocytes reflects an effective and druggable preexisting adaptive antitumor immune response in colorectal cancer, irrespective of the microsatellite status

The density of Tbet+ tumor-infiltrating T lymphocytes reflects an effective and druggable preexisting adaptive antitumor immune response in colorectal cancer, irrespective of the microsatellite status

Perioperative changes of inflammation-based biomarker for predicting the prognosis in colorectal cancer patients: a retrospective analysis

An osteopontin/CD44 immune checkpoint controls CD8+ T cell activation and tumor immune evasion

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