Abstract 1370: Antibodies derived from patient tumors augment response to immune checkpoint blockade in cancer

作者：Manoj Chelvanambi, Monika A. Zelazowska, Somnath Paul, Joshua B. Plummer, Brenda Melendez, Sarah B. Johnson, Elise F. Nassif, Laurence P. Diggs, Rossana Lazcano, Khalida Wani, Davis R. Ingram, Bharat Singh, Diana Shamsutdinova, Rebecca Soto, Florentia Dimitriou, Michael G. White, Matthew Lastrapes, Golnaz Morad, Melissa Simper, Fabiana J. Veguilla, Y David Seo, Beth A. Helmink, Russell G. Witt, Bin Liu, Nadim J. Ajami, Tullia C. Bruno, Wolf H. Fridman, James P. Allison, Padmanee Sharma, Emily Z. Keung, Tina Cascone, Christina L. Roland, Alexander J. Lazar, Kevin M. McBride, Jennifer A. Wargo · 发表于：Cancer Research · 年份：2025 · DOI：10.1158/1538-7445.am2025-1370 · 被引用次数：2 · 研究领域：Cancer Immunotherapy and Biomarkers、Cancer Research and Treatments、Monoclonal and Polyclonal Antibodies Research

Abstract Background: Immune checkpoint blockade (ICB) has revolutionized treatments for cancer; however, only a minority of patients achieve a durable response. Landmark studies have now shown that B-cells and Tertiary Lymphoid Structures (TLS) within the tumor typify exceptional response to ICB. However, the functional role of B-cells and TLS in cancer remains largely unexplored. Here, we produce and evaluate the therapeutic efficacy of tumor-derived antibodies alone or in combination with ICB-based regimen. Methods and Results: Tumors from high-risk resectable melanoma patients treated with neoadjuvant ICB were analyzed. Major pathologic response (MPR), defined as <10% viable tumor at the time of surgery, was used to evaluate response (R - responder; NR - non-responder). Formalin-fixed paraffin-embedded (FFPE) surgical resections were analyzed on NanoString GeoMx. TLS+ regions of interest (ROI) were selected based on melanoma (S100B) and immune markers (CD45 and CD20). Principal component (PC) analysis of ∼18, 000 probes revealed distinct transcriptional profiles between R and NR TLS, with PC1 strongly correlating with response status (r=0.88, p<0.0001). Differential immune analysis showed that R TLS were enriched for CD8+ T-cells (p<0.001), NK cells (p=0.004), γδ T-cells (p=0.017), and memory B-cells (p=0.026). Pathway analysis indicated an upregulation of NK-cell mediated cytotoxicity pathways in R TLS. Targeted BCR sequencing performed on fresh surgi...