Tumor MHC Class I Expression Associates with Intralesional IL2 Response in Melanoma.

Area of Science:

• Immunology
• Oncology
• Proteomics

Background:

• Cancer immunotherapy, particularly with interleukin-2 (IL2), can induce durable tumor regression.
• Predictive biomarkers for treatment response in cancer immunotherapy are not well-defined, hindering personalized treatment strategies.

Purpose of the Study:

• To identify predictive biomarkers for response to IL2 immunotherapy in melanoma.
• To explore the cellular and molecular characteristics of lesions that predict complete tumor regression.

Main Methods:

• Single-cell proteomics, transcriptomics, and genomics were performed on matched untreated and IL2-injected melanoma metastases.
• Analysis included characterization of T-cell phenotypes, B-cell aggregates, and gene expression related to IL2 and interferon-gamma (IFNγ) response.
• Validation was conducted in an independent cohort of metastatic melanoma patients treated with IL2.

Main Results:

• Complete responders showed increased non-proliferating CD8+ T cells lacking exhaustion markers (PD-1, LAG-3, TIM-3).
• Extreme responders exhibited proliferating CD8+ T cells with an exhausted phenotype (PD-1+LAG-3+TIM-3+), B-cell aggregates, and elevated IFNγ/IL2 response genes.
• Loss of membranous MHC class I on tumor cells correlated with resistance to IL2 therapy.

Conclusions:

• Intact tumor-cell antigen presentation is essential for melanoma response to IL2.
• A multidimensional, spatial approach using clinical biospecimens can generate biomarker hypotheses for immuno-oncology.