An integrative genetic approach for the exploration of melanoma immunological interactions

Project Information

Mel-Immune

Grant agreement ID: 101094980

DOI

10.3030/101094980

EC signature date 18 April 2023

Start date 1 October 2023

End date 30 September 2028

Funded under

• European Research Council (ERC)

Total cost

€ 2 500 000,00

EU contribution

€ 2 500 000,00

Coordinated by

WEIZMANN INSTITUTE OF SCIENCE
Israel

Periodic Reporting for period 1 - Mel-Immune (An integrative genetic approach for the exploration of melanoma immunological interactions)

Reporting period: 2023-10-01 to 2026-03-31

Summary of the context and overall objectives of the project

This project addresses a critical challenge in cancer treatment: improving adoptive cell therapy (ACT) for solid tumors, where limited neoantigen presentation restricts therapeutic efficacy. Current ACT approaches face barriers including poor antigen availability, tumor microenvironment suppression, and the difficulty in targeting shared, treatment-resistant neoantigens across tumor types. In this project we innovate by discovering neoantigens such as KRAS G12V and leveraging chemotherapy to enhance antigen presentation, thereby improving ACT efficacy in tumors with scarce neoantigens. The primary objective is to identify novel, recurrent neoantigens—such as KRAS G12V—and develop T cell receptors (TCRs) capable of specifically recognizing these targets, thereby enhancing the precision and potency of ACT.
To overcome resistance and heterogeneity in metastatic cancers, we developed SpotNeoMet, a data-driven pipeline that systematically detects recurrent neoantigens associated with treatment resistance. This innovative approach supports the discovery of shared immunogenic peptides and cognate TCRs, expanding immunotherapy options for patients with resistant tumors.
Furthermore, by integrating genomics, immunopeptidomics, and structural modeling, we explored aberrant peptides arising from dysregulated protein translation, revealing new immune targets and introducing a new immunotherapy axis. We uncovered key immune escape mechanisms, such as macrophage migration inhibitory factor (MIF), providing potential therapeutic targets in immune-resistant cancers.
The expected impact of this research is significant—advancing the understanding of tumor-immune interactions and offering translational strategies to improve ACT efficacy in challenging solid tumor contexts. These advances hold promise to overcome current barriers in immunotherapy, expanding treatment accessibility and improving outcomes for patients with resistant or heterogeneous tumors.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

We identified KRAS G12V as a novel recurrent neoantigen and characterized TCR T104, a T cell receptor specifically recognizing and eliminating KRAS G12V-expressing tumor cells. We demonstrated that combining T-cell therapy with lymphodepleting chemotherapy enhances tumor killing by boosting immunoproteasome activity and HLA-I expression, which remodels tumor antigen presentation. This synergy improves ACT efficacy in tumors with scarce neoantigens.
A major technical advance was the development of SpotNeoMet, an innovative data-driven pipeline systematically identifying neoantigens in treatment-resistant tumors. Using SpotNeoMet, the team discovered seven resistance-associated mutations with predicted HLA-presented neoantigens, including novel peptides from the androgen receptor H875Y mutation. The project successfully isolated cognate TCRs that target these cancer cells both in vitro and in vivo.
The exploration of aberrant peptides from impaired translation via TYW2 deletion uncovered immunogenic out-of-frame peptides enhancing tumor immunogenicity and sensitivity to anti–PD-1 therapy. This novel axis expands the repertoire of tumor antigens for immunotherapy.
Further, immune escape mechanisms were dissected through multi-modal immunophenotyping and CRISPR screening, revealing macrophage migration inhibitory factor (MIF) as a key regulator of tumor aggressiveness, offering a new therapeutic target in immune-resistant cancers.
Methodological developments include integrated genomics and immunopeptidomics for neoantigen discovery, paired in vitro and in vivo chemotherapy-immunopeptidomics pipelines, and structural modeling of TCR–pMHC complexes explaining TCR cross-reactivity across KRAS mutations. These achievements collectively present breakthrough advances for enhancing immunotherapy precision and effectiveness.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

Firstly, we overturned the traditional view that lymphodepleting chemotherapy acts only through immune depletion or microenvironmental effects by demonstrating a direct and targetable enhancement of antigen presentation in tumor cells. This new mechanistic insight explains previously unexplained synergies between immune checkpoint inhibitors (ICI) and adoptive cell therapy (ACT), opening new avenues for optimizing chemo-immunotherapy combinations.
Secondly, the project developed SpotNeoMet, the first systematic pipeline to identify recurrent neoantigens derived from resistance-driving mutations—a largely unexploited therapeutic category. This innovation enables targeted immunotherapies specifically for treatment-resistant cancers.
Thirdly, for the first time, T cell receptors (TCRs) targeting neoantigens from androgen receptor (AR) resistance mutations (AR H875Y) were validated, reframing resistant prostate cancer as a targetable disease with personalized or shared TCR therapies.
Fourthly, the discovery that silencing a translation fidelity factor induces immunogenic aberrant peptides represents a novel axis for cancer immunotherapy. This finding not only furthers cancer treatment options but also offers a new biomarker to predict immunotherapy success in patients lacking extensive mutations. More broadly, the protein translation process—with over 600 factors—offers numerous future therapeutic targets.