Association of PD-1, PD-1 ligands, and other features of the tumor immune microenvironment with response to anti-PD-1 therapy

By Janis Taube, A. Klein, J. Brahmer, Haiying Xu, Xiaoyu Pan, J. H. Kim, Lieping Chen, D. Pardoll, S. Topalian, R. Anders. Clinical Cancer Research, 2014

2,243 citations recorded by the source corpus.

Purpose: Immunomodulatory drugs differ in mechanism-of-action from directly cytotoxic cancer therapies. Identifying factors predicting clinical response could guide patient selection and therapeutic optimization. Experimental Design: Patients (N = 41) with melanoma, non–small cell lung carcinoma (NSCLC), renal cell carcinoma (RCC), colorectal carcinoma, or castration-resistant prostate cancer were treated on an early-phase trial of anti–PD-1 (nivolumab) at one institution and had evaluable pretreatment tumor specimens. Immunoarchitectural features, including PD-1, PD-L1, and PD-L2 expression, patterns of immune cell infiltration, and lymphocyte subpopulations, were assessed for interrelationships and potential correlations with clinical outcomes. Results: Membranous (cell surface) PD-L1 expression by tumor cells and immune infiltrates varied significantly by tumor type and was most abundant in melanoma, NSCLC, and RCC. In the overall cohort, PD-L1 expression was geographically associated with infiltrating immune cells (P < 0.001), although lymphocyte-rich regions were not always associated with PD-L1 expression. Expression of PD-L1 by tumor cells and immune infiltrates was significantly associated with expression of PD-1 on lymphocytes. PD-L2, the second ligand for PD-1, was associated with PD-L1 expression. Tumor cell PD-L1 expression correlated with objective response to anti–PD-1 therapy, when analyzing either the specimen obtained closest to therapy or the highest scoring sample among multiple biopsies from individual patients. These correlations were stronger than borderline associations of PD-1 expression or the presence of intratumoral immune cell infiltrates with response. Conclusions: Tumor PD-L1 expression reflects an immune-active microenvironment and, while associated other immunosuppressive molecules, including PD-1 and PD-L2, is the single factor most closely correlated with response to anti–PD-1 blockade. Clin Cancer Res; 20(19); 5064–74. ©2014 AACR.

Subfields: Immunology, Oncology, Surgery

View Paper: https://www.semanticscholar.org/paper/d544bf5dbe990d65bbe957eaef90247a1873ead0

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Immunology

1. D. Pardoll
2. Lieping Chen
3. J. Wolchok
4. W. Zou
5. S. Topalian
6. G. Freeman
7. Charles G. Drake
8. G. Dranoff

In Oncology

1. Lieping Chen
2. D. Pardoll
3. J. Wolchok
4. W. Zou
5. G. Freeman
6. S. Topalian
7. Charles G. Drake
8. G. Dranoff

In Surgery

1. J. Engelman
2. S. Demaria

Citations in the corpus

• The vigorous immune microenvironment of microsatellite instable colon cancer is balanced by multiple counter-inhibitory checkpoints (2014, neutral): “Surprisingly, in contrast to other cancers such as melanoma, renal cancer and lung cancer (19), there was virtually no discernable PD-L1 expression on tumor cells of MSI tumors by IHC; rather, co-staining with CD163 demonstrated that the majority of PD-L1 expression was by myeloid cells.”
• The evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer: recommendations by an International TILs Working Group 2014. (2015, background): “Recently, new therapies that reactivate anticancer immune responses to cancer, for example in melanomas and lung cancer, have entered clinical practice and have improved outcome [4, 5].”
• Adaptive resistance to therapeutic PD-1 blockade is associated with upregulation of alternative immune checkpoints (2016, background): “Expression of PD-L1 in tumour cells and infiltrating immune cells and PD-1 in tumour-infiltrating T cells has been associated with responsiveness to blockade of this immune checkpoint 1,7–10 ; however, mechanisms of both de novo and adaptive resistance to therapy are unclear.”
• PD-1 Blockade in Tumors with Mismatch-Repair Deficiency (2015, neutral): “The expression of PD-1 ligands (PD-L1 or PD-L2) on the surface of tumor cells or immune cells is an important — but not a definitive — predictive biomarker of response to PD-1 blockade.(4,6-8,11) In reports of the effects of PD-1 blockade in human tumors, only 1 of 33 patients with colorectal cancer”
• PD-L1 (B7-H1) and PD-1 Pathway Blockade for Cancer Therapy: Mechanisms, Response Biomarkers and Combinations (2016, background): “In support of this, a correlation has been observed between the expression of tumor tissue PD-L1 and the likelihood of the response to anti-PD therapy in patients with melanoma (48, 51), NSCLC (66), and RCC (41).”
• STING agonist formulated cancer vaccines can cure established tumors resistant to PD-1 blockade (2015, background): “Recent reports that cumulatively demonstrated colocalization of CD3, IFNg, and PD-L1 in multiple human tumor types complement our mechanistic studies on the induction of PD-L1 on tumor cells (40).”