Extended Data Fig. 4: Modeling of the timing of CD8 infiltration and the pathological assessment of areas of melanoma regression.

a) Proposed model for the timing of the anti-tumour CD8 T-cell response (numbers are not based upon real data), captured by on-therapy tumour biopsies collected day 28–35 following the start of combination therapy. The red line indicates the changes of CD8 T cell density with respect to the change in tumour cell density (blue line). The grey regions demonstrate the timing captured across on-therapy biopsies from patients who respond to nivolumab plus ipilimumab, where some biopsies captured the peak or maximum CD8 T cell density. Others were collected following the regression of the majority of the tumour, where few CD8 T cells and few melanoma cells remaining, consistent with pathological features of melanoma regression (for example tumour necrosis, fibrosis, presence of melanophages). b) Example of patient-matched screening and on-therapy biopsies. Biopsies collected from a patient who had a complete response to nivolumab plus ipilimumab were stained for CD8 T cells using immunohistochemistry (IHC). The on-therapy biopsy contained residual tumour cells in addition to very high CD8 T cell infiltration. c) Example of patient-matched screening and on-therapy biopsies, stained for CD8 T-cells using IHC, where the biopsies of a patient with complete response to nivolumab plus ipilimumab showed pathological features consistent with melanoma regression. Indicated are areas of tumour necrosis and fibrosis (blue) and tumour regression with residual CD8 T cell infiltration (red).