Clinical impact of programmed cell death ligand 1 expression in colorectal cancer

Droeser, Raoul A.; Hirt, Christian; Viehl, Carsten T.; Frey, Daniel M.; Nebiker, Christian A.; Huber, Xaver; Zlobec, Inti; Eppenberger‐Castori, Serenella; Tzankov, Alexandar; Rosso, Raffaele; Zuber, Markus; Muraro, Manuele Giuseppe; Amicarella, Francesca; Cremonesi, Eleonora; Heberer, Michael; Iezzi, Giovanna; Lugli, Alessandro; Terracciano, Luigi; Sconocchia, Giuseppe; Oertli, Daniel; Spagnoli, Giulio C.; Tornillo, Luigi

doi:10.1016/j.ejca.2013.02.015

Cited by 399 publications

(350 citation statements)

References 45 publications

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“…Our data for colon cancer also appear to differ from those reported by Droeser and colleagues who reported more frequent expression of PD-L1 in the MSS than in MSI-H colon cancers (23). The discrepancy may be caused by the fact that tested MSI-H and MSS cases differed significantly in regard to the tumor stage as the majority of MSI-H was at stage I and II, whereas MSS tumors were predominantly stage III and IV.…”

Section: Discussioncontrasting

confidence: 57%

Programmed Cell Death 1 (PD-1) and Its Ligand (PD-L1) in Common Cancers and Their Correlation with Molecular Cancer Type

Gatalica

Snyder

Maney

et al. 2014

Cancer Epidemiology, Biomarkers &Amp; Prevention

453

263

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Cancer cells expressing PD-1 ligands (PD-L1/PD-L2) inhibit immune-modulatory T-cell activation facilitating disease progression. Preliminary clinical trials exploring interruption of PD-1/PD-L1 signaling showed benefit in several cancer types. We analyzed the distribution of PD-1-positive tumor-infiltrating lymphocytes (TIL) and cancer cells' expression of PD-L1 in a molecularly profiled cohort of 437 malignancies (380 carcinomas, 33 sarcomas, and 24 melanomas). We showed that the presence of PD-1 þ TILs significantly varied among cancer types (from 0% in extraskeletal myxoid chondrosarcomas to 93% in ovarian cancer), and was generally associated with the increased number of mutations in tumor cells (P ¼ 0.029). Cancer cell expression of PD-L1 varied from absent (in Merkel cell carcinomas) to 100% (in chondro-and liposarcomas), but showed the inverse association with the number of detected mutations (P ¼ 0.004). Both PD-1 and PD-L1 expression were significantly higher in triple-negative breast cancers (TNBC) than in non-TNBC (P < 0.001 and 0.017, respectively). Similarly, MSI-H colon cancers had higher PD-1 and PD-L1 expression than the microsatellite stable tumors (P ¼ 0.002 and 0.02, respectively). TP53-mutated breast cancers had significantly higher PD-1 positivity than those harboring other driver mutations (e.g., PIK3CA; P ¼ 0.002). In non-small cell lung cancer, PD-1/PD-L1 coexpression was identified in 8 cases (19%), which lacked any other targetable alterations (e.g., EGFR, ALK, or ROS1). Our study demonstrated the utility of exploring the expression of two potentially targetable immune checkpoint proteins (PD-1/PD-L1) in a substantial proportion of solid tumors, including some aggressive subtypes that lack other targeted treatment modalities. Cancer Epidemiol Biomarkers Prev; 23(12); 2965-70. Ó2014 AACR.

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Section: Discussioncontrasting

confidence: 57%

Programmed Cell Death 1 (PD-1) and Its Ligand (PD-L1) in Common Cancers and Their Correlation with Molecular Cancer Type

Gatalica

Snyder

Maney

et al. 2014

Cancer Epidemiology, Biomarkers &Amp; Prevention

453

263

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“…Multivariate analysis showed that PD-L1/PD-L2 mRNA overexpression was an independent prognostic factor negatively influencing the prognosis of patients with CRC. Thus, our results demonstrate PD-L gene overexpression as an independent prognostic factor in CRC and confirm clinical data in solid tumors [30][31][32][33]. Consequently, PD-L expression is suggestive to be involved in downregulating anti-tumor immunity and thus promoting further tumor growth and metastasis in patients with CRC.…”

Section: Discussionsupporting

confidence: 70%

“…However, PD-L1 expression in CRC has not been fully addressed so far. Nevertheless, a strong correlation between PD-L1 expression on tumor cells and discrepant clinical outcomes has been observed [30,33]. Thus, the predictive value of PD-L1 expression on tumor cells is still controversial in CRC patients.…”

Section: Discussionmentioning

confidence: 99%

Clinical Significance and Therapeutic Potential of the Programmed Death Ligand-1 (PD-L1) and PD-L2 Expression in Human Colorectal Cancer

Gasser¹,

Koenigshausen²,

Grimm³

et al. 2017

J Cancer Sci Ther

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Purpose: The programmed death-1/programmed death ligand (PD-1/PD-L) pathway in T cell activation has been shown to play an important role in tumor evasion from host immunity. The predictive value of PD-L1 and PD-L2 expression in colorectal cancer (CRC) remains still under discussion. We analyzed whether negative signaling of infiltrating PD-1-positive T cells through PD-L1 and PD-L2 within the tumor could promote further tumor progression through downregulation of anti-tumor immunity. Methods:We investigated PD-L1 and PD-L2 expression in tumors from patients with CRC and analyzed its prognostic significance with respect to outcome analysis. Conclusion:The presented results from primary tumors and CRC patient outcome analysis suggest that negative signaling of infiltrating PD-1-positive T cells through PD-L1 expression within the tumor may promote further tumor progression through downregulation of anti-tumor immunity. Co-expression of PD-1 on CD4/Foxp3-positive T cells was found indicating T regulatory cell-mediated mechanisms by which tumor cells can evade immune recognition and destruction. This study demonstrates the importance of strategies inhibiting negative PD-1/ PD-L1 signaling in CRC.

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“…found that strong PD-L1 expression in CRC cells correlated with improved survival only in patients with MSS tumours, and that high PD-L1 was associated with an increased CD8 + T cell infiltration. 18 They hypothesized that the favourable impact of PD-L1 in MSS tumours might be coupled with the concomitant dense cytotoxic T cell infiltration. This may also explain the results from the present study, as there was a significant correlation between a high density of CD8 + T cells and high PD-L1 expression in MSS tumours.…”

Section: Discussionmentioning

confidence: 99%

Expression of programmed cell death protein 1 (PD-1) and its ligand PD-L1 in colorectal cancer: Relationship with sidedness and prognosis

et al. 2018

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Expression of programmed cell death protein 1 (PD-1) and its ligand PD-L1 has been demonstrated to confer a prognostic value in colorectal cancer (CRC), but no studies have investigated whether this association differs according to tumour location. In this study, immunohistochemical expression of PD-1 and PD-L1 was analysed in tissue microarrays with primary tumours from 557 incident CRC cases from a prospective population-based cohort. Univariable and multivariable Cox regression analyses, adjusted for age, sex, TNM stage, differentiation grade and vascular invasion, were applied to determine the impact of biomarker expression on 5-year overall survival (OS), in the entire cohort and in subgroup analysis of right colon, left colon, and rectum. High PD-L1 expression on tumour-infiltrating immune cells was an independent factor of a prolonged OS in the entire cohort (hazard ratio [HR] = 0.49; 95% confidence interval [CI] CI 0.35 – 0.68), and in tumours of the right colon (HR = 0.43; 95% CI 0.25 – 0.74) and the left colon (HR = 0.28; 95% CI 0.13 – 0.61), but not in rectal cancer. Tumour-specific PD-L1-expression was not prognostic, neither in the full cohort nor according to tumour location. High immune cell-specific PD-1 expression was associated with a prolonged OS in the entire cohort and in tumours of the right colon, but not in the left colon or rectum, and only in univariable analysis. In conclusion, these results demonstrate that immune cell-specific PD-L1 and PD-1 expression is prognostic in a site-dependent manner, whereas tumour-specific PD-L1-expression is not prognostic in CRC.

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Clinical impact of programmed cell death ligand 1 expression in colorectal cancer

Cited by 399 publications

References 45 publications

Programmed Cell Death 1 (PD-1) and Its Ligand (PD-L1) in Common Cancers and Their Correlation with Molecular Cancer Type

Programmed Cell Death 1 (PD-1) and Its Ligand (PD-L1) in Common Cancers and Their Correlation with Molecular Cancer Type

Clinical Significance and Therapeutic Potential of the Programmed Death Ligand-1 (PD-L1) and PD-L2 Expression in Human Colorectal Cancer

Expression of programmed cell death protein 1 (PD-1) and its ligand PD-L1 in colorectal cancer: Relationship with sidedness and prognosis

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