Cellular Neighborhoods Govern Antitumor T-cell Infiltration Following Anti-CTLA-4 in Melanoma with Primary Resistance to Anti-PD-1.

In the phase II trial SWOG S1616 (NCT03033576), patients with advanced melanoma with primary resistance to anti-programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) therapies had improved outcomes with the combination of the anti-cytotoxic T lymphocyte-associated protein 4 (CTLA-4) antibody ipilimumab with continued anti-PD-1 therapy with nivolumab, compared with ipilimumab alone. Baseline biopsies from patients responsive to combination therapy showed 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 exhibited networks of activated CD8 T cells near melanoma cells, whereas others had T and myeloid cells, reflecting different time points 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-CTLA-4, and plasma cell sheets in nonresponding biopsies. SIGNIFICANCE: Patients with melanoma with primary resistance to anti-PD-1/PD-L1 therapies are treated with anti-PD-1 in combination with anti-CTLA-4. Melanoma biopsies responding to combination immunotherapy in the second line of care have distinct tumor microenvironments, with antitumor immune responses, compared with those that progress, which have impaired T-cell infiltration and plasma cell networks.