The Programmed Death-1 Immune-Suppressive Pathway: Barrier to Antitumor Immunity

Ostrand‐Rosenberg, Suzanne; Horn, Lucas A.; Haile, Samuel

doi:10.4049/jimmunol.1401572

Cited by 189 publications

(157 citation statements)

References 78 publications

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“…Discussion PD-L1 expression by tumor cells has been shown to provide a mechanism of immune evasion through downregulation of the active T-cell-mediated immune response. 12,13 In this study, we demonstrate that although PD-L1 expression is infrequent in sporadic colorectal carcinomas, it is associated with signatures of the serrated pathway of colorectal carcinogenesis, including BRAF mutation, microsatellite instability, poor differentiation (with medullary morphology), and frequent tumor-infiltrating lymphocytes. 14 By multivariate analysis, PD-L1 expression is independently associated with medullary morphology and frequent tumor-infiltrating lymphocytes, and shows a trend towards association with BRAF mutation.…”

Section: Pd-l1 Expression In Colorectal Cancermentioning

confidence: 99%

PD-L1 expression in colorectal cancer is associated with microsatellite instability, BRAF mutation, medullary morphology and cytotoxic tumor-infiltrating lymphocytes

et al. 2016

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Programmed cell death 1 (PD-1) and its ligand (PD-L1) are key suppressors of the cytotoxic immune response. PD-L1 expression on tumor cells may be induced by the immune microenvironment, resulting in immune escape (adaptive immune resistance), and an adverse prognosis in many malignancies. In colorectal carcinoma the response to PD-1/PD-L1 inhibition is correlated with microsatellite instability. However, little is known about the clinicopathologic, molecular, and prognostic characteristics of colorectal carcinoma with PD-L1 expression. We performed immunohistochemistry for PD-L1 on 181 cases of colorectal carcinoma with known microsatellite instability and mutational status, and correlated PD-L1 expression with clinicopathologic features including tumor-infiltrating lymphocyte burden/immunophenotype, tumor mutational profile, and disease-specific survival. PD-L1 was expressed in tumors from 16 patients (9%) who were more often older (P = 0.006) and female (P = 0.035), with tumors exhibiting a larger size (P = 0.013), but lower stage (Po0.001). PD-L1 expression was associated with increased CD8 and TBET-positive tumor-infiltrating lymphocytes, medullary phenotype, poor differentiation, microsatellite instability, BRAF mutation (Po 0.001 for each), and a lower frequency of KRAS mutation (P = 0.012). On multivariate analysis, PD-L1 expression was associated with medullary morphology and frequent CD8-positive tumor-infiltrating lymphocytes, suggesting adaptive immune resistance. PD-L1 positivity was not predictive of survival in the entire cohort, but it was associated with a lower disease-specific survival within the microsatellite-instability high cohort. PD-L1 expression in colorectal carcinoma is associated with clinicopathologic and molecular features of the serrated pathway of colorectal carcinogenesis, and is associated with a worse outcome within microsatellite-unstable tumors. These findings support the role of PD-L1 expression in providing normally immunogenic colorectal carcinoma a means of immune evasion and a more aggressive biology, provide a potential mechanistic explanation for the favorable response of microsatellite-unstable colorectal carcinoma to PD-1/PD-L1 pathway blockade, and suggest potential predictive and prognostic roles of PD-L1 immunohistochemistry in colorectal carcinoma.

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Section: Pd-l1 Expression In Colorectal Cancermentioning

confidence: 99%

PD-L1 expression in colorectal cancer is associated with microsatellite instability, BRAF mutation, medullary morphology and cytotoxic tumor-infiltrating lymphocytes

et al. 2016

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“…How (and why) are these cells retained? Previous work has outlined a wide range of mechanisms of T cell suppression that can act in solid tumors toward programming dysfunction of these cells: metabolites made by cell types collectively described as myeloid-derived suppressor cells (36), IL-4 and IL-10 produced by TAMs (37), expression of IL-10 and TGF-β by Foxp3 + regulatory CD4 T cells (38), the expression of inhibitory checkpoint signaling pathways by tumor cells (e.g., PD1/PDL1) (39), and general physiological effects of rapidly growing tissues (e.g., hypoxia and low nutrient levels; refs. 40,41).…”

Section: Discussionmentioning

confidence: 99%

Tumor-infiltrating lymphocytes are dynamically desensitized to antigen but are maintained by homeostatic cytokine

Boldajipour¹,

Nelson²,

Krummel³

2016

JCI Insight

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“…Binding of PD-L1 to PD-1 transduces an inhibitory signal to the T cell, resulting in inhibition of T-cell proliferation, reduced secretion of effector cytokines, and potentially exhaustion. By upregulating PD-L1 expression levels, tumor cells are capable of escaping immune recognition and attack (2)(3)(4).…”

Section: Introductionmentioning

confidence: 99%

Noninvasive Imaging of Tumor PD-L1 Expression Using Radiolabeled Anti–PD-L1 Antibodies

et al. 2015

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Antibodies that block the interaction between programmed death ligand 1 (PD-L1) and PD-1 have shown impressive antitumor activity. Patients with tumors expressing PD-L1 are most likely to respond to this treatment. The aim of our study was to develop a noninvasive imaging technique to determine tumor PD-L1 expression in vivo. This could allow selection of patients that are most likely to benefit from anti-PD-1/PD-L1 treatment and to monitor PD-L1 expression during therapy. The monoclonal antibody PD-L1.3

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The Programmed Death-1 Immune-Suppressive Pathway: Barrier to Antitumor Immunity

Cited by 189 publications

References 78 publications

PD-L1 expression in colorectal cancer is associated with microsatellite instability, BRAF mutation, medullary morphology and cytotoxic tumor-infiltrating lymphocytes

PD-L1 expression in colorectal cancer is associated with microsatellite instability, BRAF mutation, medullary morphology and cytotoxic tumor-infiltrating lymphocytes

Tumor-infiltrating lymphocytes are dynamically desensitized to antigen but are maintained by homeostatic cytokine

Noninvasive Imaging of Tumor PD-L1 Expression Using Radiolabeled Anti–PD-L1 Antibodies

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