An integrative genetic approach for the exploration of melanoma immunological interactions

Introduction

Immunotherapy, which has revolutionized cancer treatment, largely relies on the immune system’s recognition of neopeptides, degradation products of altered proteins specific to cancer cells presented on their surface. In particular, cancer vaccines targeting neopeptides have shown promising clinical results.

Research Objectives

Yet, to optimize their efficacy and broaden their application, we need to decipher the nature of the cancer peptide landscape (immunopeptidome) and delineate the neopeptide properties required to induce a potent immune response. The overarching goal of this proposal is to provide an unprecedented, thorough, multifaceted understanding of the mechanisms underlying aberrant peptide production, peptide-MHC presentation, and T-cell recognition in melanoma.

Key Avenues of Research

We will do so by pursuing three key avenues:

1. Systematic interrogation of the cancer immunopeptidome to identify novel canonical and non-canonical cancer antigens and quantify their presentation (Aim 1).
2. Comprehensive functional assessment of the intrinsic qualities of actionable antigens by quantitatively charting the immunopeptidome in-vivo, while considering peptide presentation levels, clonality, and cross-presentation; and delineating how these neoantigen qualities impact the immune response (Aim 2).
3. Establish controlled in-vivo models to tease apart neoantigen qualities for the establishment of rational cancer vaccine modalities (Aim 3).

Methodology

In this effort, we will draw upon our pioneering tools and advanced mapping of the cancer peptidome in melanoma, which has already revealed novel antigenic sources. Our research approach combines:

• Comprehensive quantitative immunopeptidomics
• Novel imaging and computational approaches
• Advanced functional assays
• Novel mouse models

Expected Outcomes

Our project will provide a fresh view of melanoma-immune interactions, new research tools and pipelines, cancer-specific antigen targets for immunotherapy, and, more broadly, a paradigm for addressing similarly complex questions in other cancers.