Mathematical and Mouse Models Identify Regulatory T-cell Influx as a Key Determinant of Acquired Resistance to PD-1 Immunotherapy.

Treg influx into tumors is identified as a key determinant of acquired resistance to PD-1 immunotherapy in an immunogenic melanoma mouse model.

• Why it matters: Understanding which tumor–immune interactions drive escape from checkpoint blockade is difficult with experiments alone, especially when multiple cell types interact dynamically.
• What they did: A mechanistic, structurally identifiable mathematical model of CD8+ T cells, Tregs, dendritic cells, and tumor cells was fit to experimental data from PD-1–resistant immunogenic melanoma mice, generating many “virtual mouse” parameter sets.
• The result: Model predictions that initial tumor/immune conditions and optimal starting immune-cell ratios shape control were experimentally validated, and Treg influx specifically predicted resistance to PD-1 therapy.

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