Overcoming Immune Evasion in Melanoma

Abstract

Melanoma is the most aggressive and dangerous form of skin cancer that develops from transformed melanocytes. It is crucial to identify melanoma at its early stages, in situ, as it is "curable" at this stage. However, after metastasis, it is difficult to treat and the five-year survival is only 25%. In recent years, a better understanding of the etiology of melanoma and its progression has made it possible for the development of targeted therapeutics, such as vemurafenib and immunotherapies, to treat advanced melanomas. In this review, we focus on the molecular mechanisms that mediate melanoma development and progression, with a special focus on the immune evasion strategies utilized by melanomas, to evade host immune surveillances. The proposed mechanism of action and the roles of immunotherapeutic agents, ipilimumab, nivolumab, pembrolizumab, and atezolizumab, adoptive T- cell therapy plus T-VEC in the treatment of advanced melanoma are discussed. In this review, we implore that a better understanding of the steps that mediate melanoma onset and progression, immune evasion strategies exploited by these tumor cells, and the identification of biomarkers to predict treatment response are critical in the design of improved strategies to improve clinical outcomes for patients with this deadly disease.

Keywords: T-VEC; adoptive T-cell therapy; anti-CTLA-4; anti-PD-1; anti-PD-L1; immune checkpoint blockade therapy; immunotherapy; melanoma; melanoma immune evasion.

Figure 1

Melanoma can be segregated into distinct subtypes, based on anatomical location, sun exposure, and genetic profiles, which affect treatment responses to MAPK, PI3K/AKT, receptor tyrosine kinase inhibitors, and immunotherapies. CSID—Chronically Sun Induced melanoma; non-CSID—Non-Chronically Sun Induced melanoma; and triple WT—Triple Wild-Type. Created with BioRender.com.

Figure 2

Various melanoma therapies used in the clinic. These therapies include the standard treatments along with the precursors for modern-day immunotherapies, followed by “targeted” immunotherapy. Created with BioRender.com.

Figure 3

A summary of the immune dysfunctions that contribute to melanoma development and progression. Created with BioRender.com.

Figure 4

Biomarkers for immune checkpoint blockade therapy (A) and adoptive T-cell therapy (B) that can improve stratification of melanoma patients into responders and non-responders. Created with BioRender.com.

Figure 5

Cutaneous melanoma patients benefit from immune checkpoint blockade therapy better than non-cutaneous melanoma patients. Created with BioRender.com.

Figure 6

Non-cutaneous melanoma patients benefit from adoptive T-cell therapy better than cutaneous melanoma patients. Created with BioRender.com.

Figure 7

Mechanistic-driven design of combination immunotherapies. Ipilimumab plus nivolumab are approved for the treatment of metastatic melanoma, while the other three are currently under investigation or are proposed in this review. Created with BioRender.com.