Targeting inflamed and non-inflamed melanomas: biological background and clinical challenges

Indini, Alice; Massi, Daniela; Pirro, Matteo; Roila, Fausto; Grossi, Francesco; Sahebkar, Amirhossein; Glodde, Nicole; Bald, Tobias; Mandalà, Mario

doi:10.1016/j.semcancer.2022.06.005

Cited by 18 publications

(7 citation statements)

References 146 publications

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“…For this reason, they usually respond to ICB therapies. However, not all patients respond, indicating that immune cell infiltration is not sufficient to induce an effective immune response probably caused by T cell exhaustion ( 22 ). Therapies with ICB have shown promise in melanoma ( 23 ), non-small-cell lung cancer (NSCLC) ( 22 , 24 ) and urothelial cancer ( 25 , 26 ), which are examples of the inflamed subtype.…”

Section: Immune Exclusionmentioning

confidence: 99%

“…However, not all patients respond, indicating that immune cell infiltration is not sufficient to induce an effective immune response probably caused by T cell exhaustion ( 22 ). Therapies with ICB have shown promise in melanoma ( 23 ), non-small-cell lung cancer (NSCLC) ( 22 , 24 ) and urothelial cancer ( 25 , 26 ), which are examples of the inflamed subtype. The immune-excluded tumors present no infiltration of CD8+ T cells to the tumor core, but have accumulation of them around tumor margins, and are resistant to multiple types of treatment ( 27 ).…”

Section: Immune Exclusionmentioning

confidence: 99%

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Cancer immune exclusion: breaking the barricade for a successful immunotherapy

et al. 2023

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Immunotherapy has changed the course of cancer treatment. The initial steps were made through tumor-specific antibodies that guided the setup of an antitumor immune response. A new and successful generation of antibodies are designed to target immune checkpoint molecules aimed to reinvigorate the antitumor immune response. The cellular counterpart is the adoptive cell therapy, where specific immune cells are expanded or engineered to target cancer cells. In all cases, the key for achieving positive clinical resolutions rests upon the access of immune cells to the tumor. In this review, we focus on how the tumor microenvironment architecture, including stromal cells, immunosuppressive cells and extracellular matrix, protects tumor cells from an immune attack leading to immunotherapy resistance, and on the available strategies to tackle immune evasion.

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Section: Immune Exclusionmentioning

confidence: 99%

Section: Immune Exclusionmentioning

confidence: 99%

Cancer immune exclusion: breaking the barricade for a successful immunotherapy

et al. 2023

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“…One of the most validated GEPs is the IFN-gamma signature, referring to all the transcriptomics sequences that reflect T-cell activation and INF-gamma production. INF-gamma production is critical for innate and adaptive immune activation in melanoma but has a role also in differentiation as well as in tumor cell apoptosis and senescence [ 35 ]. This pathway is influenced by various factors, including tumor microenvironment composition features, such as TILs level, T-cell phenotype, and the presence of myeloid-derived suppressor cells [ 35 ].…”

Section: First Line Predictive/prognostic Factorsmentioning

confidence: 99%

Predictive Factors in Metastatic Melanoma Treated with Immune Checkpoint Inhibitors: From Clinical Practice to Future Perspective

Poletto,

Paruzzo,

Nepote

et al. 2023

Cancers

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The introduction of immunotherapy revolutionized the treatment landscape in metastatic melanoma. Despite the impressive results associated with immune checkpoint inhibitors (ICIs), only a portion of patients obtain a response to this treatment. In this scenario, the research of predictive factors is fundamental to identify patients who may have a response and to exclude patients with a low possibility to respond. These factors can be host-associated, immune system activation-related, and tumor-related. Patient-related factors can vary from data obtained by medical history (performance status, age, sex, body mass index, concomitant medications, and comorbidities) to analysis of the gut microbiome from fecal samples. Tumor-related factors can reflect tumor burden (metastatic sites, lactate dehydrogenase, C-reactive protein, and circulating tumor DNA) or can derive from the analysis of tumor samples (driver mutations, tumor-infiltrating lymphocytes, and myeloid cells). Biomarkers evaluating the immune system activation, such as IFN-gamma gene expression profile and analysis of circulating immune cell subsets, have emerged in recent years as significantly correlated with response to ICIs. In this manuscript, we critically reviewed the most updated literature data on the landscape of predictive factors in metastatic melanoma treated with ICIs. We focus on the principal limits and potentiality of different methods, shedding light on the more promising biomarkers.

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“…Together with antigen creation and presentation, the main condition for the immune system to be enhanced by ICIs is the presence of an abundant and functionally active immune infiltrate within the TME [ 65 ]. Immunologically “hot tumors” display an abundant T cell effector infiltration, as well as a genetic signature characterized by intense expression of cytolytic and IFN-γ related genes [ 66 , 67 , 68 ].…”

Section: Mechanisms Underlying Response and Resistance To Icismentioning

confidence: 99%

NAD/NAMPT and mTOR Pathways in Melanoma: Drivers of Drug Resistance and Prospective Therapeutic Targets

Indini

Fiorilla

Ponzone

et al. 2022

IJMS

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Malignant melanoma represents the most fatal skin cancer due to its aggressive behavior and high metastatic potential. The introduction of BRAF/MEK inhibitors and immune-checkpoint inhibitors (ICIs) in the clinic has dramatically improved patient survival over the last decade. However, many patients either display primary (i.e., innate) or develop secondary (i.e., acquired) resistance to systemic treatments. Therapeutic resistance relies on the rewiring of multiple processes, including cancer metabolism, epigenetics, gene expression, and interactions with the tumor microenvironment that are only partially understood. Therefore, reliable biomarkers of resistance or response, capable of facilitating the choice of the best treatment option for each patient, are currently missing. Recently, activation of nicotinamide adenine dinucleotide (NAD) metabolism and, in particular, of its rate-limiting enzyme nicotinamide phosphoribosyltransferase (NAMPT) have been identified as key drivers of targeted therapy resistance and melanoma progression. Another major player in this context is the mammalian target of rapamycin (mTOR) pathway, which plays key roles in the regulation of melanoma cell anabolic functions and energy metabolism at the switch between sensitivity and resistance to targeted therapy. In this review, we summarize known resistance mechanisms to ICIs and targeted therapy, focusing on metabolic adaptation as one main mechanism of drug resistance. In particular, we highlight the roles of NAD/NAMPT and mTOR signaling axes in this context and overview data in support of their inhibition as a promising strategy to overcome treatment resistance.

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Targeting inflamed and non-inflamed melanomas: biological background and clinical challenges

Cited by 18 publications

References 146 publications

Cancer immune exclusion: breaking the barricade for a successful immunotherapy

Cancer immune exclusion: breaking the barricade for a successful immunotherapy

Predictive Factors in Metastatic Melanoma Treated with Immune Checkpoint Inhibitors: From Clinical Practice to Future Perspective

NAD/NAMPT and mTOR Pathways in Melanoma: Drivers of Drug Resistance and Prospective Therapeutic Targets

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