| Title | Clonal tracing reveals diverse patterns of response to immune checkpoint blockade |
| Authors | Gu, Shengqing Stan Wang, Xiaoqing Hu, Xihao Jiang, Peng Li, Ziyi Traugh, Nicole Bu, Xia Tang, Qin Wang, Chenfei Zeng, Zexian Fu, Jingxin Meyer, Cliff Zhang, Yi Cejas, Paloma Lim, Klothilda Wang, Jin Zhang, Wubing Tokheim, Collin Sahu, Avinash Das Xing, Xiaofang Kroger, Benjamin Ouyang, Zhangyi Long, Henry Freeman, Gordon J. Brown, Myles Liu, X. Shirley |
| Affiliation | Dana Farber Canc Inst, Dept Data Sci, Boston, MA 02215 USA Harvard TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA 02215 USA Dana Farber Canc Inst, Ctr Funct Canc Epigenet, Boston, MA 02215 USA Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA Harvard Med Sch, Boston, MA 02115 USA Tongji Univ, Shanghai Pulm Hosp, Sch Life Sci & Technol, Clin Translat Res Ctr, Shanghai 200433, Peoples R China Peking Univ, Canc Hosp & Inst, Canc Translat Res Lab, Div Gastrointestinal, Beijing 100142, Peoples R China Univ Texas Southwestern Med Sch, Dallas, TX 75390 USA |
| Keywords | CD8(+) T-CELLS PD-1 BLOCKADE ACQUIRED-RESISTANCE ANTITUMOR IMMUNITY CLINICAL ACTIVITY CTLA-4 BLOCKADE DENDRITIC CELLS TUMOR-CELLS CHIP-SEQ B-CELLS |
| Issue Date | 15-Oct-2020 |
| Publisher | GENOME BIOLOGY |
| Abstract | Background Immune checkpoint blockade (ICB) therapy has improved patient survival in a variety of cancers, but only a minority of cancer patients respond. Multiple studies have sought to identify general biomarkers of ICB response, but elucidating the molecular and cellular drivers of resistance for individual tumors remains challenging. We sought to determine whether a tumor with defined genetic background exhibits a stereotypic or heterogeneous response to ICB treatment. Results We establish a unique mouse system that utilizes clonal tracing and mathematical modeling to monitor the growth of each cancer clone, as well as the bulk tumor, in response to ICB. We find that tumors derived from the same clonal populations showed heterogeneous ICB response and diverse response patterns. Primary response is associated with higher immune infiltration and leads to enrichment of pre-existing ICB-resistant cancer clones. We further identify several cancer cell-intrinsic gene expression signatures associated with ICB resistance, including increased interferon response genes and glucocorticoid response genes. These findings are supported by clinical data from ICB treatment cohorts. Conclusions Our study demonstrates diverse response patterns from the same ancestor cancer cells in response to ICB. This suggests the value of monitoring clonal constitution and tumor microenvironment over time to optimize ICB response and to design new combination therapies. Furthermore, as ICB response may enrich for cancer cell-intrinsic resistance signatures, this can affect interpretations of tumor RNA-seq data for response-signature association studies. |
| URI | http://hdl.handle.net/20.500.11897/593188 |
| ISSN | 1474-760X |
| DOI | 10.1186/s13059-020-02166-1 |
| Indexed | SCI(E) |
| Appears in Collections: | 北京肿瘤医院 |
