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Immune Cell Infiltration of the Primary Tumor, Not PD-L1 Status, Is Associated With Improved Response to Checkpoint Inhibition in Metastatic Melanoma.

ABSTRACT: Immune checkpoint inhibition has resulted in dramatic improvements in overall and relapse-free survival in patients with metastatic melanoma. The most commonly used immune checkpoint inhibitors are monoclonal antibodies targeting programmed cell death protein 1 and cytotoxic T-lymphocyte-associated protein 4. Unfortunately, a significant subset of patients fail to respond to these therapies, which has resulted in intense research efforts to identify the factors which are associated with treatment response. To this end, we investigated immune cell infiltration in primary melanomas and melanoma metastases, in addition to tumor cell PD-L1 expression, to determine whether these factors are associated with an improved outcome after immune checkpoint inhibition. Indeed, the extent of the immune cell infiltration in the primary melanoma, measured by the Immunoscore, was associated with a significantly improved response to immune checkpoint inhibition in terms of increased overall survival. However, the Immunoscore did not predict which patients would respond to treatment. The Immunoscore was significantly reduced in metastases when compared to primary melanomas. In contrast, PD-L1 expression, exhaustively tested using four commercially available anti-PD-L1 clones, did not differ significantly between primary tumors and melanoma metastases and was not associated treatment response. Whilst replication in larger, prospective studies is required, our data demonstrates the relevance of immune cell infiltration in the primary melanoma as a novel marker of improved overall survival in response to immune checkpoint inhibition.

SUBMITTER: Kumpers C

PROVIDER: S-EPMC6425878 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Immune Cell Infiltration of the Primary Tumor, Not PD-L1 Status, Is Associated With Improved Response to Checkpoint Inhibition in Metastatic Melanoma.

Kümpers Christiane C Jokic Mladen M Haase Ozan O Offermann Anne A Vogel Wenzel W Grätz Victoria V Langan Ewan A EA Perner Sven S Terheyden Patrick P

Frontiers in medicine 20190313

Immune checkpoint inhibition has resulted in dramatic improvements in overall and relapse-free survival in patients with metastatic melanoma. The most commonly used immune checkpoint inhibitors are monoclonal antibodies targeting programmed cell death protein 1 and cytotoxic T-lymphocyte-associated protein 4. Unfortunately, a significant subset of patients fail to respond to these therapies, which has resulted in intense research efforts to identify the factors which are associated with treatmen ...[more]

PMID: 30931305

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Project description:Blocking the interaction between the programmed cell death (PD)-1 protein and one of its ligands, PD-L1, has been reported to have impressive antitumor responses. Therapeutics targeting this pathway are currently in clinical trials. Pembrolizumab and nivolumab are the first of this anti-PD-1 pathway family of checkpoint inhibitors to gain accelerated approval from the US Food and Drug Administration (FDA) for the treatment of ipilimumab-refractory melanoma. Nivolumab has been associated with improved overall survival compared with dacarbazine in patients with previously untreated wild-type serine/threonine-protein kinase B-raf proto-oncogene BRAF melanoma. Although the most mature data are in the treatment of melanoma, the FDA has granted approval of nivolumab for squamous cell lung cancer and the breakthrough therapy designation to immune- checkpoint inhibitors for use in other cancers: nivolumab, an anti-PD-1 monoclonal antibody, for Hodgkin lymphoma, and MPDL-3280A, an anti-PD-L1 monoclonal antibody, for bladder cancer and non-small cell lung cancer. Here we review the literature on PD-1 and PD-L1 blockade and focus on the reported clinical studies that have included patients with melanoma.PubMed was searched to identify relevant clinical studies of PD-1/PD-L1-targeted therapies in melanoma. A review of data from the current trials on clinicaltrial.gov was incorporated, as well as data presented in abstracts at the 2014 annual meeting of the American Society of Clinical Oncology, given the limited number of published clinical trials on this topic.The anti-PD-1 and anti-PD-L1 agents have been reported to have impressive antitumor effects in several malignancies, including melanoma. The greatest clinical activity in unselected patients has been seen in melanoma. Tumor expression of PD-L1 is a suggestive, but inadequate, biomarker predictive of response to immune-checkpoint blockade. However, tumors expressing little or no PD-L1 are less likely to respond to PD-1 pathway blockade. Combination checkpoint blockade with PD-1 plus cytotoxic T-lymphocyte antigen (CTLA)-4 blockade appears to improve response rates in patients who are less likely to respond to single-checkpoint blockade. Toxicity with PD-1 blocking agents is less than the toxicity with previous immunotherapies (eg, interleukin 2, CTLA-4 blockade). Certain adverse events can be severe and potentially life threatening, but most can be prevented or reversed with close monitoring and appropriate management.This family of immune-checkpoint inhibitors benefits not only patients with metastatic melanoma but also those with historically less responsive tumor types. Although a subset of patients responds to single-agent blockade, the initial trial of checkpoint-inhibitor combinations has reported a potential to improve response rates. Combination therapies appear to be a means of increasing response rates, albeit with increased immune-related adverse events. As these treatments become available to patients, education regarding the recognition and management of immune-related effects of immune-checkpoint blockade will be essential for maximizing clinical benefit.

Project description:BackgroundThe immunotherapy with immune checkpoints inhibitors (ICI) has changed the life expectancy in metastatic melanoma (MM) patients. Nevertheless, several patients do not respond hence, the identification and validation of novel biomarkers of response to ICI is of crucial importance. Circulating extracellular vesicles (EVs) such as PD-L1+ EV mediate resistance to anti-PD1, instead the role of PD1+ EV is not fully understood.MethodsWe isolated the circulating EVs from the plasma of an observational cohort study of 71 metastatic melanoma patients and correlated the amount of PD-L1+ EVs and PD1+ EVs with the response to ICI. The analysis was performed according to the origin of EVs from the tumor and the immune cells. Subsequently, we analysed the data in a validation cohort of 22 MM patients to assess the reliability of identified EV-based biomarkers. Additionally we assessed the involvement of PD1+ EVs in the seizure of nivolumab and in the perturbation of immune cells-mediated killing of melanoma spheroids.ResultsThe level of PD-L1+ EVs released from melanoma and CD8+ T cells and that of PD1+ EVs irrespective of the cellular origin were higher in non-responders. The Kaplan-Meier curves indicated that higher levels of PD1+ EVs were significantly correlated with poorer progression-free survival (PFS) and overall survival (OS). Significant correlations were found for PD-L1+ EVs only when released from melanoma and T cells. The multivariate analysis showed that high level of PD1+ EVs, from T cells and B cells, and high level of PD-L1+ EVs from melanoma cells, are independent biomarkers of response. The reliability of PD-L1+ EVs from melanoma and PD1+ EVs from T cells in predicting PFS was confirmed in the validation cohort through the univariate Cox-hazard regression analysis. Moreover we discovered that the circulating EVs captured nivolumab and reduced the T cells trafficking and tumor spheroids killing.ConclusionOur study identified circulating PD1+ EVs as driver of resistance to anti-PD1, and highlighted that the analysis of single EV population by liquid biopsy is a promising tool to stratify MM patients for immunotherapy.

Dataset Information

Immune Cell Infiltration of the Primary Tumor, Not PD-L1 Status, Is Associated With Improved Response to Checkpoint Inhibition in Metastatic Melanoma.

Publications

Immune Cell Infiltration of the Primary Tumor, Not PD-L1 Status, Is Associated With Improved Response to Checkpoint Inhibition in Metastatic Melanoma.

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