Tumor antigen–specific CD8 T cells infiltrating the tumor express high levels of PD-1 and are functionally impaired

Ahmadzadeh, Mojgan; Johnson, Laura A.; Heemskerk, Bianca; Wunderlich, John R.; Dudley, Mark E.; White, Donald E.; Rosenberg, Steven A.

doi:10.1182/blood-2008-12-195792

Cited by 1,525 publications

(1,228 citation statements)

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“…This suggestion may account for the clinical implication that a high PD-1 + /CD8 + tumorinfiltrating lymphocyte ratio is a poor prognostic factor for pulmonary adenocarcinomas in this study. Moreover, it has been demonstrated that the main subset of tumor-infiltrating immune cells expressing PD-1 were CD8 + rather than CD4 + T cells, [14][15][16]49 supporting that PD-1 + cells in pulmonary adenocarcinomas are primarily CD8 + T cells. Thus, it is reasonable that high PD-1 + /CD8 + tumor-infiltrating lymphocyte ratios and PD-L1 expression in tumors might inhibit specific immune responses against tumor cells that may be a useful parameter for unfavorable prognosis of patients with pulmonary adenocarcinoma.…”

Section: Discussionmentioning

confidence: 92%

“…6,8,13 Furthermore, PD-1 + T cells were observed in tumor tissues and were functionally impaired upon engagement by PD-L1 or PD-L2. [14][15][16] As with CTLA-4, blockade of the PD-1/PD-L pathway enhanced antitumor immune responses by restoring T-cell functions. 11 Consistently, blockade of PD-1 or PD-L1 controlled the progression of various cancers and prolonged the survival of advanced pulmonary adenocarcinoma patients in clinical trials.…”

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confidence: 99%

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Clinicopathologic analysis of programmed cell death-1 and programmed cell death-ligand 1 and 2 expressions in pulmonary adenocarcinoma: comparison with histology and driver oncogenic alteration status

et al. 2015

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Immunotherapies targeting the programmed cell death-1/programmed cell death-ligand 1 pathway have emerged as promising therapeutic strategies for lung cancer. However, the expression pattern and prognostic implications of programmed cell death-ligand 1 and 2 and programmed cell death-1 in comparison with the histology and genetic alterations in pulmonary adenocarcinomas remains unclear and thus were addressed here. Programmed cell death-ligand 1 and 2 expression in tumor cells and the quantities of programmed cell death-1 + and CD8 + tumor-infiltrating lymphocytes were immunohistochemically evaluated in 497 resected pulmonary adenocarcinomas and analyzed according to clinicopathological and genetic statuses. Programmed cell death-ligand 1 and 2 expression were observed in 59% and 64% of pulmonary adenocarcinomas, respectively, and showed a strong positive correlation with each other (Po 0.001). Programmed cell death-ligand 1 expression was higher in nodal metastasis cases (P = 0.006), smokers (P = 0.056), poorly differentiated tumors and histologic subtypes of solid and micropapillary patterns (Po0.001). There was no significant difference in programmed cell death-ligand 1 and 2 expression according to EGFR mutation status. However, programmed cell death-ligand 1 expression was correlated with ALK translocation (P = 0.054) and expression of EGFR and MET (Po 0.001). Meanwhile, programmed cell death-ligand 2 expression was correlated with ALK translocation (P = 0.052), and expression of MET (Po 0.001) and ERBB2 (P = 0.013). The numbers of CD8 + and programmed cell death-1 + lymphocytes were higher in smokers (P = 0.012 and 0.016) and MET-expressing adenocarcinomas (Po 0.001). Patients expressing programmed cell death-ligand 1 and/or high ratios of programmed cell death-1 + /CD8 + lymphocytes showed shorter disease-free survival (P = 0.001). Our study demonstrated that programmed cell death-ligand 1 and 2 expression varied with histology, EGFR, ALK, MET, and ERBB2 statuses, and activation of the programmed cell death-1/programmed cell death-ligand 1 pathway may be a poor prognostic factor in pulmonary adenocarcinomas.

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Section: Discussionmentioning

confidence: 92%

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confidence: 99%

Clinicopathologic analysis of programmed cell death-1 and programmed cell death-ligand 1 and 2 expressions in pulmonary adenocarcinoma: comparison with histology and driver oncogenic alteration status

et al. 2015

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“…T-cells with an exhausted phenotype can also be found following chronic antigen stimulation in tumors 19,[36][37][38] . Despite showing this phenotype, there is a clear positive correlation between number of CD8 + tumor infiltrating lymphocytes (TIL) and a favorable clinical prognosis 39,40 .…”

Section: Evidence That Functional T-cells Are Maintained In Chronic Imentioning

confidence: 99%

T cell differentiation in chronic infection and cancer: functional adaptation or exhaustion?

et al. 2014

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Chronic viral infections and malignant tumours induce T cells that have a reduced ability to secrete effector cytokines and have upregulated expression of the inhibitory receptor PD1 (programmed cell death protein 1). These features have so far been considered to mark terminally differentiated 'exhausted' T cells. However, several recent clinical and experimental observations indicate that phenotypically exhausted T cells can still mediate a crucial level of pathogen or tumour control. In this Opinion article, we propose that the exhausted phenotype results from a differentiation process in which T cells stably adjust their effector capacity to the needs of chronic infection. We argue that this phenotype is optimized to cause minimal tissue damage while still mediating a critical level of pathogen control. In contrast to the presently held view of functional exhaustion, this new concept better reflects the pathophysiology and clinical manifestations of persisting infections, and it provides a rationale for emerging therapies that enhance T cell activity in chronic infection and cancer by blocking inhibitory receptors. Daniel T. Utzschneider Division of Immunology and Allergy of the Lausanne University Hospital (CHUV) and Swiss Vaccine Research Institute (SVRI), Lausanne, SwitzerlandDaniel Utzschneider is a PhD student of Dietmar Zehn. His research is focused on T-cell differentiation in chronic infection. Susanne G. Oberle Division of Immunology and Allergy of the Lausanne University Hospital (CHUV) and Swiss Vaccine Research Institute (SVRI), Lausanne, SwitzerlandSusanne Oberle is a PhD student of Dietmar Zehn. Her research interests are focused on investigating T-cell responses in acute and chronic infections. and it provides a rational for emerging therapies that enhance T-cell activity in chronic infection and cancer by blocking inhibitory receptors. Christian Münz PhD

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“…Second, specificity may be limited to private (i.e., nonshared) antigens resulting from novel mutations 12. Third, the functional competence of infiltrating lymphocytes may be compromised 11, 13. The latter two observations have strongly influenced recent advances in immunotherapy.…”

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confidence: 99%

Translation and Clinical Development of Bispecific T‐cell Engaging Antibodies for Cancer Treatment

Yuraszeck

Kasichayanula

Benjamin

2017

Clin Pharma and Therapeutics

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Bispecific T‐cell Engagers (BiTE®) antibody constructs enable a polyclonal T‐cell response to cell‐surface tumor‐associated antigens, bypassing the narrow specificities of T‐cell receptors and the need for antigen presentation through the major histocompatibility complex pathways. Blinatumomab, a CD19xCD3 BiTE® antibody construct, received accelerated approval for the treatment of relapsed/refractory Philadelphia chromosome negative acute lymphoblastic leukemia. Herein we review the pharmacology, safety, and efficacy observed in studies of blinatumomab and other BiTE® antibody constructs. Quantitative systems pharmacology is envisioned as a means to optimize dosing decisions for trials in which BiTE® antibody constructs are administered as monotherapy or in combination with other immunotherapies.

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Tumor antigen–specific CD8 T cells infiltrating the tumor express high levels of PD-1 and are functionally impaired

Cited by 1,525 publications

References 44 publications

Clinicopathologic analysis of programmed cell death-1 and programmed cell death-ligand 1 and 2 expressions in pulmonary adenocarcinoma: comparison with histology and driver oncogenic alteration status

Clinicopathologic analysis of programmed cell death-1 and programmed cell death-ligand 1 and 2 expressions in pulmonary adenocarcinoma: comparison with histology and driver oncogenic alteration status

T cell differentiation in chronic infection and cancer: functional adaptation or exhaustion?

Translation and Clinical Development of Bispecific T‐cell Engaging Antibodies for Cancer Treatment

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