Association of PD-1, PD-1 Ligands, and Other Features of the Tumor Immune Microenvironment with Response to Anti–PD-1 Therapy

Abstract

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 pre-treatment 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.

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

“…The results from the present study, with immune cell-specific PD-L1 expression being an independent prognostic factor while its expression in tumour cells was not, are coherent with previous research 16 , 23-26 and demonstrate that PD-L1 expression in immune cells and tumour cells might carry different prognostic values and might be regulated by distinct mechanisms. Furthermore, although tumour cell-specific PD-L1 expression has been validated as a predictive marker for response to PD-1 or PD-L1 blockade in several cancers, 11 , 38 , 39 recent studies now suggest that PD-L1 expression in tumour-infiltrating myeloid and T cells also play a critical role in immunosuppression, 38 , 40-43 and should possibly be taken into account in assessment scoring for PD-1/PD-L1 blockade.…”

“…Furthermore, tumour cell-specific expression of PD-L1 was significantly associated with immune cell-specific PD-1 and PD-Ll expression, supporting results from other studies. 39 …”

Combination with SGT-53 overcomes tumor resistance to a checkpoint inhibitor

“…Although the elements involved in tumor response are complex, 10 studies seeking biomarkers that might be used to predict response to anti-PD1 antibody have found that tumor expression of PD-L1 is the single feature most highly correlated with response. 49,50 It has been suggested that cancer patients who do not respond to treatment with anti-PD1 antibodies are those having tumors with relatively low expression of PD-L1. 2, 50–52 Our experiments revealed that SGT-53 treatment up-regulated PD-L1 expression in cultured 4T1 cells and in mouse syngeneic breast tumors in vivo .…”

Programmed Death-Ligand 1 Expression, Microsatellite Instability, Epstein–Barr Virus, and Human Papillomavirus in Nasopharyngeal Carcinomas of Patients from the Philippines

“…The programmed death 1 (PD-1)/PD-ligand 1 (PD-L1) immune checkpoint is one of the mechanisms employed by cancer cells to evade T cell mediated endogenous antitumor responses [4][5][6][7]. Immunotherapy agents targeting the PD-1/PD-L1 pathway have achieved durable treatment effects in patients with various cancer types including EBV-associated malignancies [5,6,[8][9][10].…”

“…Immunotherapy agents targeting the PD-1/PD-L1 pathway have achieved durable treatment effects in patients with various cancer types including EBV-associated malignancies [5,6,[8][9][10]. Positive tumor PD-L1 expression by immunohistochemistry in pre-treatment specimens is thought to be predictive of clinical response [5,9].…”