Soluble immune checkpoints and T-cell subsets in blood as biomarkers for resistance to immunotherapy in melanoma patients

Machiraju, Devayani; Wiecken, Melanie; Lang, Nina; Hülsmeyer, Ingrid; Roth, Jasmin; Schank, Timo E; Eurich, R; Halama, Niels; Enk, Alexander H.; Hassel, Jessica C.

doi:10.1080/2162402x.2021.1926762

Cited by 47 publications

(42 citation statements)

References 37 publications

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“…However, the splice variant that lacks exon 3 codes for a soluble PD-1 (sPD1) that does not bind PD-L1 and PD-L2 but has been detected in inflammatory and autoimmune diseases. Thus, this form could be a potential biomarker for disease [ 27 , 28 ].…”

Section: Pd-1/pd-l1 In Health and Cancermentioning

confidence: 99%

Glucocorticoid and PD-1 Cross-Talk: Does the Immune System Become Confused?

Adorisio

Cannarile

Delfino

et al. 2021

Cells

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Programmed cell death protein 1 (PD-1) and its ligands, PD-L1/2, control T cell activation and tolerance. While PD-1 expression is induced upon T cell receptor (TCR) activation or cytokine signaling, PD-L1 is expressed on B cells, antigen presenting cells, and on non-immune tissues, including cancer cells. Importantly, PD-L1 binding inhibits T cell activation. Therefore, the modulation of PD-1/PD-L1 expression on immune cells, both circulating or in a tumor microenvironment and/or on the tumor cell surface, is one mechanism of cancer immune evasion. Therapies that target PD-1/PD-L1, blocking the T cell-cancer cell interaction, have been successful in patients with various types of cancer. Glucocorticoids (GCs) are often administered to manage the side effects of chemo- or immuno-therapy, exerting a wide range of immunosuppressive and anti-inflammatory effects. However, GCs may also have tumor-promoting effects, interfering with therapy. In this review, we examine GC signaling and how it intersects with PD-1/PD-L1 pathways, including a discussion on the potential for GC- and PD-1/PD-L1-targeted therapies to “confuse” the immune system, leading to a cancer cell advantage that counteracts anti-cancer immunotherapy. Therefore, combination therapies should be utilized with an awareness of the potential for opposing effects on the immune system.

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Section: Pd-1/pd-l1 In Health and Cancermentioning

confidence: 99%

Glucocorticoid and PD-1 Cross-Talk: Does the Immune System Become Confused?

Adorisio

Cannarile

Delfino

et al. 2021

Cells

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“…Recently, Machiraju demonstrated the existence of a negative correlation between the patient’s outcome to ICI treatment and the levels of soluble circulating PD1 [ 26 ], however the significance of circulating PD1 remains not fully understood. Owing the evidence that the EVs are the main source of circulating PD1 [ 24 ], we sought to understand in the same cohort of MM patients, whose data are reported in [ 25 ], whether PD1 is expressed on the membrane of circulating EVs and if a putative systemic increase of PD1 + EVs in plasma of patients may cause or correlates with unresponsiveness to anti-PD1.…”

Section: Introductionmentioning

confidence: 99%

Circulating extracellular vesicles expressing PD1 and PD-L1 predict response and mediate resistance to checkpoint inhibitors immunotherapy in metastatic melanoma

et al. 2022

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Background The 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. Methods We 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. Results The 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. Conclusion Our 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.

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“…Beyond honing the current therapeutic arsenal, melanoma targets governing resistance are also under investigation. T cell immunoglobulin and mucin domain 3 (TIM-3) and T cell immunoreceptor with Ig and ITIM domains (TIGIT) are two extensively studied immune checkpoints responsible for fortifying melanoma against current immunotherapies, especially anti-PD-1 treatments ( 47 ) and [reviewed in ( 48 – 51 )]. The human leukocyte antigen (HLA) complexes I and II are responsible for antigen presentation, a crucial factor in lymphocyte function.…”

Section: Key Players In Resistance Against Immune Checkpoint Inhibito...mentioning

confidence: 99%

Mechanisms of Immunotherapy Resistance in Cutaneous Melanoma: Recognizing a Shapeshifter

et al. 2022

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Melanoma is one of the seven most common cancers in the United States, and its incidence is still increasing. Since 2011, developments in targeted therapies and immunotherapies have been essential for significantly improving overall survival rates. Prior to the advent of targeted and immunotherapies, metastatic melanoma was considered a death sentence, with less than 5% of patients surviving more than 5 years. With the implementation of immunotherapies, approximately half of patients with metastatic melanoma now survive more than 5 years. Unfortunately, this also means that half of the patients with melanoma do not respond to current therapies and live less than 5 years after diagnosis. One major factor that contributes to lower response in this population is acquired or primary resistance to immunotherapies via tumor immune evasion. To improve the overall survival of melanoma patients new treatment strategies must be designed to minimize the risk of acquired resistance and overcome existing primary resistance. In recent years, many advances have been made in identifying and understanding the pathways that contribute to tumor immune evasion throughout the course of immunotherapy treatment. In addition, results from clinical trials focusing on treating patients with immunotherapy-resistant melanoma have reported some initial findings. In this review, we summarize important mechanisms that drive resistance to immunotherapies in patients with cutaneous melanoma. We have focused on tumor intrinsic characteristics of resistance, altered immune function, and systemic factors that contribute to immunotherapy resistance in melanoma. Exploring these pathways will hopefully yield novel strategies to prevent acquired resistance and overcome existing resistance to immunotherapy treatment in patients with cutaneous melanoma.

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Soluble immune checkpoints and T-cell subsets in blood as biomarkers for resistance to immunotherapy in melanoma patients

Cited by 47 publications

References 37 publications

Glucocorticoid and PD-1 Cross-Talk: Does the Immune System Become Confused?

Glucocorticoid and PD-1 Cross-Talk: Does the Immune System Become Confused?

Circulating extracellular vesicles expressing PD1 and PD-L1 predict response and mediate resistance to checkpoint inhibitors immunotherapy in metastatic melanoma

Mechanisms of Immunotherapy Resistance in Cutaneous Melanoma: Recognizing a Shapeshifter

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