Cellular Neighborhoods Govern Antitumor T-cell Infiltration Following Anti–CTLA-4 in Melanoma with Primary Resistance to Anti–PD-1
Year: 2026
Type: article
Abstract: 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.
Source: Cancer Discovery
Authors: Katie M. Campbell, Daniel G. Chen, Zaid E. Bustami, Nataly Naser Al Deen, Egmidio Medina, Cynthia R. Gonzalez, Jessica Maxey, Marshall A. Thompson, Sarah Samorodnitsky, Lawrence F. Kuklinski, Ivan Perez Garcilazo, Ignacio Baselga-Carretero, Agustin Vega-Crespo, Jia Ming Chen, Rangasamy Elumalai, Marc Visitacion, Rob Schiemann, Lacey Padron, Cadence Chang, Alan E. Zelin, Sai S. Chelluri, Silvia Boffo, Kari L. Kendra, Bartosz Chmielowski, Thach-Giao Truong, Nikhil I. Khushalani, Frances Collichio, Alexandra P. Ikeguchi, Adrienne I. Victor, Kim A. Margolin, Douglas B. Johnson, Yuanbin Chen, Jeffrey A. Sosman, Sapna P. Patel, Siwen Hu-Lieskovan, James Moon, Daniel K. Wells, Christine N. Spencer, Shay Bellasea, Ari M. Vanderwalde, Michael C. Wu, Philip O. Scumpia, Antoni Ribas
Institutions: University of California, Los Angeles, Parker Institute for Cancer Immunotherapy, UCLA Jonsson Comprehensive Cancer Center, Fred Hutch Cancer Center, Agilent Technologies (United States), Bristol-Myers Squibb (United States), The Ohio State University Wexner Medical Center, Kaiser Permanente, Kaiser Permanente Vallejo Medical Center, Moffitt Cancer Center, University of North Carolina at Chapel Hill, UNC Lineberger Comprehensive Cancer Center, University of Oklahoma Health Sciences Center, University of Rochester, Saint John's Health Center, Vanderbilt-Ingram Cancer Center, Northwestern University, Robert H. Lurie Comprehensive Cancer Center of Northwestern University, The University of Texas MD Anderson Cancer Center, University of Utah, Huntsman Cancer Institute
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: American Association for Cancer Research, Cancer Research Institute, V Foundation for Cancer Research, Melanoma Research Foundation, Bristol-Myers Squibb, Agilent Technologies, Melanoma Research Alliance, Parker Institute for Cancer Immunotherapy, Ressler Family Foundation, National Institutes of Health, Stand Up To Cancer, National Cancer Institute, Jonsson Comprehensive Cancer Center
Awards: G1548551769, G183821942, G1938688226, Johns Hopkins University NCTN Lead Academic Site Program, Overcoming BRAF-inhibitor Resistance in Melanoma, SWOG Network Group Operations Center of the NCTN, G6186550942, G6717269746, G7193850426, G8329150311, Alliance for Clinical Trials in Oncology Operations Center, G8834492710
OpenAlex ID: W7155043877
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