Biological Factors behind Melanoma Response to Immune Checkpoint Inhibitors

Abstract

Modern immunotherapy together with targeted therapy has revolutionized the treatment of advanced melanoma. Inhibition of immune checkpoints significantly improved the median overall survival and gave hope to many melanoma patients. However, this treatment has three serious drawbacks: high cost, serious side effects, and an effectiveness limited only to approximately 50% of patients. Some patients do not derive any or short-term benefit from this treatment due to primary or secondary resistance. The response to immunotherapy depends on many factors that fall into three main categories: those associated with melanoma cells, those linked to a tumor and its microenvironment, and those classified as individual ontogenic and physiological features of the patient. The first category comprises expression of PD-L1 and HLA proteins on melanoma cells as well as genetic/genomic metrics such as mutational load, (de)activation of specific signaling pathways and epigenetic factors. The second category is the inflammatory status of the tumor: “hot” versus “cold” (i.e., high versus low infiltration of immune cells). The third category comprises metabolome and single nucleotide polymorphisms of specific genes. Here we present up-to-date data on those biological factors influencing melanoma response to immunotherapy with a special focus on signaling pathways regulating the complex process of anti-tumor immune response. We also discuss their potential predictive capacity.

Development of an Immune-Related Gene Signature for Prognosis in Melanoma

“…Our results showed that the status of overall increased infiltrating immune cells in melanoma has the potential to predict clinical prognosis. Melanoma could be divided into ”hot” and “cold” status (enrich in or lack of immune cells infiltration), and the hot status is likely to correlate with antigen processing and higher expression of interferons, TNF and chemokines pathways ( 40 ). We further analyzed the infiltrating immune cell subtypes which correlated with the prognosis of melanoma.…”

The Functional Crosstalk between Myeloid-Derived Suppressor Cells and Regulatory T Cells within the Immunosuppressive Tumor Microenvironment

“…In accordance, the number of Treg circulating in the blood of cancer patients and the infiltration of Treg into the tumor have been documented to be closely related to the progression and prognosis of multiple cancer entities [ 20 ]. More interestingly, the extent of Treg infiltration into human tumors has been proposed to show an inverse correlation with the response to ICI therapy [ 131 , 132 ]. Not least, this observation emphasizes the importance of Treg in the understanding of the anti-tumor immunity and thus the development of novel therapeutic approaches.…”

The effect of pretreatment BMI on the prognosis and serum immune cells in advanced LSCC patients who received ICI therapy

“…However, the efficacy of ICI therapy varies greatly from patient to patient. [ 22 ] Although previous studies have shown that patients with high PD-L1, high tumor mutation burden and DNA mismatch-repair deficient/microsatellite instability-high can benefit more from ICI therapy, [ 22 – 24 ] we need to further explore the clinical factors affecting the therapeutic effect. Therefore, we started from BMI to reveal its impact on ICI therapy and the prognosis of advanced LSCC patients.…”

“…[ 22 ] Recent studies had shown that ICI therapy is more effective in tumor patients with high PD-L1 expression, high tumor mutation burden, and DNA mismatch-repair deficient /microsatellite instability-high. [ 22 – 24 ] Therefore, to find out the factors that affect the effect of ICI therapy can not only guide the choice of clinical treatment, but also explore the new direction of scientific research. Therefore, the purpose of this study is to explore the effect of pretreatment BMI on the prognosis and serum immune cells in the advanced LSCC patients who received ICI therapy.…”