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.
New immunomodulatory therapeutic targets and prognostic biomarkers hold promise in the management of melanoma. Using publicly available human melanoma datasets and bioinformatics analyses, we previously identified 21 immune-related genes that are differentially expressed in metastatic melanoma and have significant association with patient survival (Cancer Res 2021;81(13 Suppl):Abstract 873). Further, we shortlisted five candidate genes that have been implicated in pathogenesis of certain cancers; however, their role in melanoma is not known. These include, (i) Marginal Zone B and B1 cell specific protein (MZB1), an endoplasmic reticulum (ER)-localized protein that is shown to constitutively express in B cells as well as on cancer cells; (ii) SAM Domain, SH3 Domain and Nuclear Localization Signals 1 (SAMSN1), a negative regulator of B-cell activation that regulates cell spreading and cell polarization; (iii) NCK Associated Protein 1 Like (NCKAP1L) that controls lymphocyte development, activation, and proliferation, as well as phagocytosis and migration by neutrophils and macrophages; (iv) Kallikrein Related Peptidase 8 (KLK8), an epidermal protease involved in the skin barrier proteolytic cascade; and (v) Epstein Barr Virus Induced Gene 3 (EBI3) functions in innate immune responses. This study was aimed to validate the expression profile of these five proteins (MZB1, SAMSN1, NCKAP1L, KLK8 and EBI3) in clinical melanoma tissues along with S100, a melanoma biomarker. We performed fluorescent immunostaining of a human melanoma tissue microarray (ME2082c; US Biomax) consisting of 208 melanoma tissue cores (128 cases of primary malignant melanoma, 64 metastatic melanoma, 8 adjacent skin and 8 normal skin tissue) followed by multispectral Vectra Imaging coupled with inForm software analysis. Our results showed significantly increased expression of KLK8, SAMSN1 and EBI3 in S100-positive melanoma cells compared to S100-negative cells. Further, MZB1 and NCKAP1L protein levels were significantly increased in melanoma primary tumors and metastatic tissues compared to normal skin. Furthermore, an increasing trend for KLK8 and SAMSN1 proteins, though not significant, was observed in melanoma tissues. Interestingly, EBI3 expression was not found to be altered between the melanoma and skin tissues. Next, using in vitro cell culture analysis, we quantified MZB1 protein levels using Simple Western in various human melanoma cell lines and normal human melanocytes. We observed increased MZB1 protein levels in four human melanoma cell lines (A375, G361, HS294T, WM115) compared to normal melanocytes. Overall, our study suggests that MZB1 and NCKAP1L could be potential new targets for melanoma management. Additional validation and further evaluation of functional significance of these immune-related proteins using in vitro and in vivo models may lead to new prognostic and therapeutic strategies for melanoma management. Citation Format: Gagan Chhabra, Jessica Thornton, Shengqin Su, Mary A. Ndiaye, Nihal Ahmad. A tissue microarray study to validate key immune-related proteins in melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 354.
Das Melanom ist eine der sieben häufigsten Krebsarten in den USA und seine Häufigkeit nimmt weiter zu. Seit 2011 haben die Entwicklungen bei zielgerichteten Therapien und Immuntherapien wesentlich dazu beigetragen, die Gesamtüberlebensraten deutlich zu verbessern. Vor dem Aufkommen zielgerichteter Therapien und Immuntherapien galt das metastasierte Melanom als Todesurteil, denn weniger als 5% der Patienten überlebten mehr als 5 Jahre. Dank der Einführung von Immuntherapien überlebt heute etwa die Hälfte der Patienten mit metastasiertem Melanom mehr als 5 Jahre. Leider bedeutet dies auch, dass die Hälfte der Melanompatienten auf die derzeitigen Therapien nicht anspricht und nach Diagnose weniger als 5 Jahre überlebt. Ein wichtiger Faktor, der zu einem geringeren Ansprechen in dieser Bevölkerungsgruppe beiträgt, ist die erworbene oder primäre Resistenz gegen Immuntherapien, die durch eine Immunevasion des Tumors entsteht. Um das Gesamtüberleben von Melanompatienten zu verbessern, müssen neue Behandlungsstrategien entwickelt werden, die das Risiko einer erworbenen Resistenz minimieren und die bestehende primäre Resistenz überwinden. In den letzten Jahren wurden bei der Identifizierung und dem Verständnis der Signalwege viele Fortschritte gemacht, die im Verlauf einer Immuntherapie zur Immunevasion des Tumors beitragen. Darüber hinaus gibt es zur Behandlung von Patienten mit immuntherapieresistentem Melanom erste Ergebnisse aus klinischen Studien. In dieser Übersicht fassen wir wichtige Mechanismen zusammen, die bei Patienten mit kutanem Melanom zur Resistenz gegen Immuntherapien führen. Wir haben uns auf tumoreigene Merkmale der Resistenz, veränderte Immunfunktionen und systemische Faktoren konzentriert, die zur Immuntherapieresistenz beim Melanom beitragen. Die Erforschung dieser Signalwege wird hoffentlich zu neuen Strategien führen, um eine erworbene Resistenz zu verhindern und eine bestehende Resistenz gegen eine Immuntherapie bei Patienten mit kutanem Melanom zu überwinden.
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