Plasma proteomic biomarkers identify non-responders and reveal biological insights about the tumor microenvironment in melanoma patients after PD1 blockade

• DOI: 10.1101/2022.02.02.478819
• Publication Date: 2022-02-06T03:55:10Z
• Authors: Arnav Mehta; Marijana Rucevic; Emmett Sprecher; Milan Parikh; Jiajia Chen; Dennie T. Frederick; Elliot Woods; Lynn Bi; David Lieb; Lina Hultin-Rosen...; Jamey Guess; Ryan J. Park; Alexis Schneider; William Michaud; Benchun Miao; Gyulnara Kasumova; Michelle S. Kim; Xue Bai; Russell W. Jenkins; Samuel J. Klempner; Anna L. K. Gonye; Keren Yizhak; Moshe Sade-Feldman; David Liu; Ryan J. Sullivan; Keith T. Flaherty; Nir Hacohen; Genevieve M. Boland
• Keywords: 0301 basic medicine; 03 medical and health sciences; 3. Good health

AbstractMost patients treated with immune checkpoint blockade (ICB) do not have durable treatment responses. Therefore, there is a critical need to identify early non-invasive biomarkers of response. We performed plasma proteomic analysis (>700 proteins) at three timepoints on 174 metastatic melanoma patients treated with ICB. We leverage independent training and testing cohorts to build a predictor of immunotherapy response that outperforms several tissue-based approaches. We found 217 differentially expressed proteins between ICB responders (R) and non-responders (NR), including a co-regulated module of proteins enriched in certain NR patients. By analyzing single-cell RNA-sequencing data of tumor biopsies from 32 patients, we dissected the relative contribution of cells in the tumor to proteins in circulation. The majority of proteins in the co-regulated NR module derived from tumor and myeloid cells. Amongst myeloid cells, we identified a subset of tumor-associated macrophages (TAMs) with a suppressive phenotype that expressed high levels of the co-regulated NR module, thus suggesting they are key drivers of non-response signatures. Together, our data demonstrates the utility of plasma proteomics in biomarker discovery and in understanding the biology of host response to tumors.