Understanding tumor-immune-stromal dynamics driving response and resistance to immune checkpoint blockade in melanoma 4125
Abstract Description Melanoma patients treated with anti-PD1 or anti-PD1/anti-CTLA4 present intrinsic or acquired resistance to these immune checkpoint blockade (ICB) treatments. However, the interactions between tumor-stromal-immune cells in the microenvironment (TME) underlying these resistances remain unclear. In this study, we used a cohort of melanoma patients (n = 61) treated with ICB, pre-treatment (n = 33) and post-progression (n = 28), for whole-exome sequencing, single-nucleus RNA sequencing and high-resolution spatial imaging. We developed a framework to analyze response and resistance (intrinsic and acquired) via tumor-intrinsic programs, immune features, and tumor-stromal-immune interactions. Patients with low immune infiltration exhibited enrichment of macrophages associated with hypoxia and angiogenesis phenotypes. Samples with high immune infiltrates displayed an enrichment in lymphocytes, particularly TCF7+ CD8+ T cells. Pre-treatment samples from patients experiencing durable clinical benefit are encriched in memory B cells and plasmablast-like B cells.The presence of Bcells and of follicular dendritic cells in non-lymph node biopsies support the presence of tertiary lymphoid structures within the TME. Lastly, the presence of a TIMD4-expressing macrophage subset correlates with lymphocyte infiltration, indicating its potential role in promoting anti-tumor immunity. Our work defines TME immune profile interaction with tumor-stromal cells associated with clinical outcomes in melanoma. Funding Sources NCI HTAN Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)
Authors
- Sachi Krishna (ORCID: https://orcid.org/0000-0002-7457-9700)
- Ryan J. Sullivan (ORCID: https://orcid.org/0000-0001-5344-6645)
- Genevieve Marie Boland (ORCID: https://orcid.org/0000-0002-7522-6173)
- Xinyu Cui (ORCID: https://orcid.org/0000-0002-3685-7431)
- Allison Frangieh
- Tatyana Sharova (ORCID: https://orcid.org/0000-0003-2123-3906)
- Domenic Abbondanza (ORCID: https://orcid.org/0000-0002-7202-0225)
- Eliezer M. Van Allen (ORCID: https://orcid.org/0000-0002-0201-4444)
- Timothy R. Blosser (ORCID: https://orcid.org/0000-0002-7739-922X)
- Dennie T. Frederick (ORCID: https://orcid.org/0000-0003-3355-5267)
- Priyanka Solanky (ORCID: https://orcid.org/0009-0009-7374-467X)
- Tyler Aprati
- Aaron R. Thorner (ORCID: https://orcid.org/0000-0002-9160-7881)
- Bruce E. Johnson (ORCID: https://orcid.org/0000-0002-5252-3677)
- Cai McCann (ORCID: https://orcid.org/0000-0003-2010-9794)
- Scott J. Rodig (ORCID: https://orcid.org/0000-0003-1761-9769)
- Barbara E. Engelhardt (ORCID: https://orcid.org/0000-0002-6139-7334)
- Michael P. Manos (ORCID: https://orcid.org/0000-0003-0841-207X)
- Giuseppe Tarantino (ORCID: https://orcid.org/0000-0002-6078-6856)
- Kathleen L. Pfaff (ORCID: https://orcid.org/0000-0003-3311-5384)
- Alex K. Shalek (ORCID: https://orcid.org/0000-0001-5670-8778)
- F. Stephen Hodi (ORCID: https://orcid.org/0000-0001-6825-091X)
- Karla Helvie (ORCID: https://orcid.org/0000-0002-3514-0332)
- Yiwen He (ORCID: https://orcid.org/0000-0002-0223-4906)
- Xiaowei Zhuang (ORCID: https://orcid.org/0000-0002-6034-7853)
- Aleigha Lawless (ORCID: https://orcid.org/0009-0009-3861-3164)
- Elliot Boblitt
- Jiajia Chen (ORCID: https://orcid.org/0000-0002-5378-6284)
- Boyang Zhang (ORCID: https://orcid.org/0000-0002-4702-7628)
- David Liu (ORCID: https://orcid.org/0000-0003-0346-5033)
- Chanell Mangum (ORCID: https://orcid.org/0000-0002-7852-2840)
- Sami Farhi
- Hannah Mae Faulkner
Institutions
- Broad Institute (US)
- Dana-Farber Cancer Institute (US)
Publication Details
- Journal
- The Journal of Immunology
- Published
- 2025-11-01
- DOI
- https://doi.org/10.1093/jimmun/vkaf283.1846
- Primary Topic
- Cancer Immunotherapy and Biomarkers
- Type
- article
- Field-Weighted Citation Impact
- 0.00