Cellular neighborhoods govern antitumor T-cell infiltration following anti-CTLA-4 in melanoma with primary resistance to anti-PD-1.

In the phase 2 trial SWOG S1616 (NCT03033576), patients with advanced melanoma with primary resistance to anti-PD-1/L1 therapies had improved outcomes on the combination of the anti-CTLA-4 antibody ipilimumab with continued anti-PD-1 with nivolumab, over ipilimumab alone. Baseline biopsies from patients responsive to combination therapy had increased transcriptomic expression of complement by myeloid cells, interferon pathways by endothelial cells, and oxidative phosphorylation and lipid metabolism by melanoma cells. Using spatial proteomics, some on-therapy biopsies from patients responding to combination therapy had networks of activated CD8 T cells nearby melanoma cells, while others had T cells and myeloid cells, reflective of different timepoints in a dynamic antitumor response. Conversely, biopsies from patients progressing on combination immunotherapy displayed impaired T-cell infiltration adjacent to plasma cells. Our results define cellular neighborhoods and transcriptomes in melanoma biopsies when reversing resistance to anti-PD-1 with the addition of anti-CTLA4, and plasma cell sheets in non-responding biopsies.