Are Molecular Alterations Linked to Genetic Instability Worth to Be Included as Biomarkers for Directing or Excluding Melanoma Patients to Immunotherapy?

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.

Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immunotherapy for the treatment of melanoma, version 3.0

“…Although microsatellite instability-high (MSI-H) tumors commonly have a high TMB, the converse is not true. 22 While most melanomas do have a high TMB, the frequency of MSI-H is much lower. In a small study, only 11% of 56 primary cutaneous melanomas and 21% of 42 metastatic melanomas were MSI-H. 23 Mismatch repair protein deficiency (dMMR) has been reported in around 13% of cutaneous melanomas, with pathologically-relevant MMR deficiency rates of <1% for uveal melanoma.…”

Mechanisms of Immunotherapy Resistance in Cutaneous Melanoma: Recognizing a Shapeshifter

“…Consistent with this theory, high TMB is generally associated with improved overall survival and immunotherapy response in melanoma patients ( 8 , 86 – 88 , 107 ). However, there is still some debate about a good way to make high and low TMB definitions more consistent across studies to improve its use as a biomarker for immunotherapy response [reviewed in ( 108 , 109 )]. Recent research has shown that TMB and neoantigen burden scores can predict response and likelihood of resistance to immunotherapies ( 110 ).…”

The Emerging Burden of Genetic Instability and Mutation in Melanoma: Role of Molecular Mechanisms

“…Despite recent groundbreaking advances in the treatment of cutaneous melanoma, it remains one of the most treatment-resistant malignancies [ 21 ]. Immunotherapies represent an alternative to molecular targeted therapies.…”