Prognostic impact of programed cell death-1 (PD-1) and PD-ligand 1 (PD-L1) expression in cancer cells and tumor infiltrating lymphocytes in colorectal cancer

Li, Yaqi; Liang, Lei; Dai, Weixing; Cai, Guoxiang; Xu, Ye; Li, Xinxiang; Li, Qingguo; Cai, Sanjun

doi:10.1186/s12943-016-0539-x

Cited by 239 publications

(221 citation statements)

References 36 publications

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“…Whereas immune cell-specific PD-L1 expression was found to be an independent prognostic factor, tumour cell-specific PD-L1 expression was not associated with survival neither in the full cohort nor in subgroup analysis according to PTL, supporting previous reports in CRC 16 , 17 , 19 , 22 and other cancers. 32-34 Nonetheless, an abundance of studies have reported high PD-L1 expression to be associated with an impaired prognosis due to induction of immune evasion, 6 , 7 , 35 being the rationale for PD-1/PD-L1 blockade.…”

Section: Discussionsupporting

confidence: 80%

“…17 , 19 , 22 Moreover, in subsite analysis according to PTL, PD-L1 expression was independently associated with a prolonged survival in patients with right-sided and left-sided colon cancers, but not in patients with rectal cancer. These findings further support previous evidence suggesting that proximal and distal CRC may represent different epidemiological, pathological, genetic, and clinical entities.…”

Section: Discussionmentioning

confidence: 92%

“…demonstrated PD-1 to be an independent prognostic factor for both OS and disease-free survival in patients with MSS tumours. 17 Moreover, PD-1 expression has been demonstrated to carry an independent favourable impact in gastric, 47 ovarian, 48 and head and neck cancer, 49 among others. Further studies are warranted to elucidate the prognostic impact of PD-1 expression in CRC, particularly regarding PTL.…”

Section: Discussionmentioning

confidence: 99%

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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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Section: Discussionsupporting

confidence: 80%

Section: Discussionmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 99%

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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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“…10,26 Unlike most tumors, in which PD-1 overexpression clearly correlates with impaired survival, PD-1 expressions seems to be paradoxically associated with improved outcome in primary CRC. 10,11 This is possibly based on specific features of the intestine immune system, which is constantly exposed to commensal microbiota. Furthermore, expression of PD-L1 in primary rectal cancer has been shown to be rare or even absent.…”

Section: Discussionmentioning

confidence: 99%

“…PD-1 and PD-L1 expressing tumor-infiltrating lymphocytes (TIL) at the primary tumor site lead to prolonged recurrence free and overall survival. 10,11 This unique finding in CRC has been controversially discussed in the literature and is explained by the gut specific microenvironment and particular features of the intestinal immune system.…”

Section: Introductionmentioning

confidence: 99%

494 PD1-positive tumor-infiltrating lymphocytes are associated with poor clinical outcome after pulmonary metastasectomy for colorectal cancer

Chang

Ignatova

Kollmann³

et al. 2018

Journal of Investigative Dermatology

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Pulmonary metastasectomy (PM) is routinely performed in colorectal cancer (CRC) patients with oligometastatic spreading to the lungs. Patients with an aggressive tumor phenotype should be excluded from PM, since its benefit is outweighed by early tumor recurrence and impaired prognosis. Expression of PD-1 and its ligands are prognostic factors in a variety of primary tumors. However, their impact on patients' outcome in the setting of PM for CRC has not been evaluated before. 53 CRC patients with pulmonary metastases receiving PM with curative intent were included in this study. Tissue samples of resected pulmonary metastases and available corresponding primary tumors were collected and assessed for PD-1, PD-L1 and PD-L2 expression by tumor-infiltrating lymphocytes (TILs) and tumor cells. Expression patterns were correlated with clinical outcome parameters. PD-1 and PD-L1 expression was commonly found in TILs and tumor cells. Expression levels significantly differed between metastases and primary tumors. High PD-1 expression by TILs was associated with impaired overall survival (low vs high expression (mean, 95% CI): 78 mo (60-96) vs 35 mo (25-44); p = 0.011). Additionally, the subgroup of patients, who experienced an upgrading in their TILs/PD1 status between primary and metastasis had a worse survival outcome compared with patients with the same grade or a downgrading (34 mo (26-42) vs 96 mo (72-120); p = 0.004). Thus, PD-1 expression by TILs is a strong prognostic marker in CRC patients with pulmonary spreading treated by PM. Moreover, this study provides a rationale for a therapeutic PD-1 pathway blockade in the treatment of CRC lung metastases. Future, large-scale studies are warranted to validate the findings of this single-center, retrospective analysis. Conclusions PD-1 expression by TILs is a strong prognostic marker in CRC patients with pulmonary spreading treated by PM. Moreover, this study provides a rationale for a therapeutic PD-1 pathway blockade in the treatment of CRC lung metastases. Further studies are warranted to confirm these findings in a larger study cohort

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Transcriptomic Analyses of Pretreatment Tumor Biopsy Samples, Response to Neoadjuvant Chemoradiotherapy, and Survival in Patients With Advanced Rectal Cancer

et al. 2023

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ImportanceNeoadjuvant chemoradiotherapy (CRT) is the standard of care for advanced rectal cancer. Yet, estimating response to CRT remains an unmet clinical challenge.ObjectiveTo investigate and better understand the transcriptomic factors associated with response to neoadjuvant CRT and survival in patients with advanced rectal cancer.Design, Setting, and ParticipantsA single-center, retrospective, case series was conducted at a comprehensive cancer center. Pretreatment biopsies from 298 patients with rectal cancer who were later treated with neoadjuvant CRT between April 1, 2004, and September 30, 2020, were analyzed by RNA sequencing. Data analysis was performed from July 1, 2021, to May 31, 2022.ExposuresChemoradiotherapy followed by total mesorectal excision or watch-and-wait management.Main Outcomes and MeasuresTranscriptional subtyping was performed by consensus molecular subtype (CMS) classification. Immune cell infiltration was assessed using microenvironment cell populations-counter (MCP-counter) scores and single-sample gene set enrichment analysis (ssGSEA). Patients with surgical specimens of tumor regression grade 3 to 4 or whose care was managed by the watch-and-wait approach for more than 3 years were defined as good responders.ResultsOf the 298 patients in the study, 205 patients (68.8%) were men, and the median age was 61 (IQR, 52-67) years. Patients classified as CMS1 (6.4%) had a significantly higher rate of good response, albeit survival was comparable among the 4 subtypes. Good responders exhibited an enrichment in various immune-related pathways, as determined by ssGSEA. Microenvironment cell populations-counter scores for cytotoxic lymphocytes were significantly higher for good responders than nonresponders (median, 0.76 [IQR, 0.53-1.01] vs 0.58 [IQR, 0.43-0.83]; P &lt; .001). Cytotoxic lymphocyte MCP-counter score was independently associated with response to CRT, as determined in the multivariable analysis (odds ratio, 3.81; 95% CI, 1.82-7.97; P &lt; .001). Multivariable Cox proportional hazards regression analysis, including postoperative pathologic factors, revealed the cytotoxic lymphocyte MCP-counter score to be independently associated with recurrence-free survival (hazard ratio [HR], 0.38; 95% CI, 0.16-0.92; P = .03) and overall survival (HR, 0.16; 95% CI, 0.03-0.83; P = .03).Conclusions and RelevanceIn this case series of patients with rectal cancer treated with neoadjuvant CRT, the cytotoxic lymphocyte score in pretreatment biopsy samples, as computed by RNA sequencing, was associated with response to CRT and survival. This finding suggests that the cytotoxic lymphocyte score might serve as a biomarker in personalized multimodal rectal cancer treatment.

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Prognostic impact of programed cell death-1 (PD-1) and PD-ligand 1 (PD-L1) expression in cancer cells and tumor infiltrating lymphocytes in colorectal cancer

Cited by 239 publications

References 36 publications

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

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

494 PD1-positive tumor-infiltrating lymphocytes are associated with poor clinical outcome after pulmonary metastasectomy for colorectal cancer

Transcriptomic Analyses of Pretreatment Tumor Biopsy Samples, Response to Neoadjuvant Chemoradiotherapy, and Survival in Patients With Advanced Rectal Cancer

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