Melanosomes as cancer immune modulators: a novel paradigm in melanoma immunity

Introduction

Despite remarkable progress in treating melanoma, the most lethal of human skin cancers, 50% of patients are treatment-resistant, with most experiencing disease recurrence. Our recent unpublished clinical and experimental findings uncover new, yet to be explored, melanosome contributions to cancer immunity unique to melanoma.

Melanosome Characteristics

Melanoma retains, for mostly unknown reasons, the ability of its origin to produce melanosomes, lineage-specific large extracellular vesicles (EVs) containing melanin. Surprisingly, our preliminary findings indicate that:

1. Melanosomes bind and block T-cell activity in a T-cell receptor/antigen-dependent manner.
2. Melanosomes carry a neoantigen signature that is distinct from their cell of origin.
3. Melanosomes can be recycled by stroma cells, with each type endowing the melanosomes with a distinct signature, which may modulate, upon engulfment by macrophages, the latter’s phenotype in relation to melanoma.

Research Proposal

Given our novel findings and body of literature that strongly suggest an immune role for melanosomes, we here propose to comprehensively explore, for the first time, melanosomes’ effect on melanoma immunity in three directions:

• Aim 1: Melanosomes’ interaction with T-cells.
• Aim 2: Influence on melanoma immune recognition.
• Aim 3: Interaction with macrophages.

This will be achieved by a strong research framework involving new experimental tools, fresh human samples, and cutting-edge in-vivo, molecular, cellular, and computational models.

Project Impact

While of tremendous complexity and scale, this project is set to offer new perspectives on melanoma progression and response to therapy. Further, our novel EV concepts will greatly advance the EV field and can also be applied to other physiological systems.

Contributions to the Scientific Community

Our project will also offer the scientific community new experimental tools and omics data on melanoma EVs and immunity. Finally, our project will provide new potential therapeutic means to overcome melanoma immunotherapy resistance and block melanoma progression.