Abstract
The improvement of the immunotherapeutic potential in most human cancers, including melanoma, requires the identification of increasingly detailed molecular features underlying the tumor immune responsiveness and acting as disease-associated biomarkers. In recent past years, the complexity of the immune landscape in cancer tissues is being steadily unveiled with a progressive better understanding of the plethora of actors playing in such a scenario, resulting in histopathology diversification, distinct molecular subtypes, and biological heterogeneity. Actually, it is widely recognized that the intracellular patterns of alterations in driver genes and loci may also concur to interfere with the homeostasis of the tumor microenvironment components, deeply affecting the immune response against the tumor. Among others, the different events linked to genetic instability—aneuploidy/somatic copy number alteration (SCNA) or microsatellite instability (MSI)—may exhibit opposite behaviors in terms of immune exclusion or responsiveness. In this review, we focused on both prevalence and impact of such different types of genetic instability in melanoma in order to evaluate whether their use as biomarkers in an integrated analysis of the molecular profile of such a malignancy may allow defining any potential predictive value for response/resistance to immunotherapy.
Highlights
The increasing efficacy of immunotherapy with immune checkpoint inhibitors (ICIs) has deeply changed life expectancy for different types of fatal cancer: melanoma, lung cancer, renal carcinoma, advanced squamous cell carcinoma of the head and neck or skin districts, some colorectal cancers, and refractory lymphomas [1,2,3,4,5]
Multidisciplinary approaches have significantly increased the quest for an even more accurate molecular classification through the assessment of the mutational status in multiple oncogenes and tumor suppressor genes; in the immuno-oncological field, such efforts have already produced some approved tests (PD-L1 expression and microsatellite instability rates) and other advanced tests yet to be fully proven for efficacy [5, 8,9,10]
Toward a holistic approach aimed at implementing precision oncology for treatment of “difficult” human cancers, should evaluation of genetic instability be included into the patients’ molecular classification, probably even for the cancer types—like cutaneous melanoma—with a recognized low prevalence of such an alteration? In supporting a positive answer to this question, it has been recently demonstrated that a detailed tumor molecular profiling with identification of all low-frequency actionable alterations in pancreatic cancer—a definitely difficult-to-treat tumor—may produce a significant benefit from receiving a matched therapy [11]
Summary
The improvement of the immunotherapeutic potential in most human cancers, including melanoma, requires the identification of increasingly detailed molecular features underlying the tumor immune responsiveness and acting as disease-associated biomarkers. The complexity of the immune landscape in cancer tissues is being steadily unveiled with a progressive better understanding of the plethora of actors playing in such a scenario, resulting in histopathology diversification, distinct molecular subtypes, and biological heterogeneity. The different events linked to genetic instability—aneuploidy/somatic copy number alteration (SCNA) or microsatellite instability (MSI)—may exhibit opposite behaviors in terms of immune exclusion or responsiveness. We focused on both prevalence and impact of such different types of genetic instability in melanoma in order to evaluate whether their use as biomarkers in an integrated analysis of the molecular profile of such a malignancy may allow defining any potential predictive value for response/resistance to immunotherapy
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