Clonal tracing reveals diverse patterns of response to immune checkpoint blockade
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 resis...
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doaj-b3244746e20a48e2bb9e322dbec655a32020-11-25T03:53:44ZengBMCGenome Biology1474-760X2020-10-0121112810.1186/s13059-020-02166-1Clonal tracing reveals diverse patterns of response to immune checkpoint blockadeShengqing Stan Gu0Xiaoqing Wang1Xihao Hu2Peng Jiang3Ziyi Li4Nicole Traugh5Xia Bu6Qin Tang7Chenfei Wang8Zexian Zeng9Jingxin Fu10Cliff Meyer11Yi Zhang12Paloma Cejas13Klothilda Lim14Jin Wang15Wubing Zhang16Collin Tokheim17Avinash Das Sahu18Xiaofang Xing19Benjamin Kroger20Zhangyi Ouyang21Henry Long22Gordon J. Freeman23Myles Brown24X. Shirley Liu25Department of Data Science, Dana-Farber Cancer InstituteCenter for Functional Cancer Epigenetics, Dana-Farber Cancer InstituteDepartment of Data Science, Dana-Farber Cancer InstituteDepartment of Data Science, Dana-Farber Cancer InstituteDepartment of Data Science, Dana-Farber Cancer InstituteDepartment of Data Science, Dana-Farber Cancer InstituteDepartment of Medical Oncology, Dana-Farber Cancer InstituteCenter for Functional Cancer Epigenetics, Dana-Farber Cancer InstituteDepartment of Data Science, Dana-Farber Cancer InstituteDepartment of Data Science, Dana-Farber Cancer InstituteDepartment of Data Science, Dana-Farber Cancer InstituteDepartment of Data Science, Dana-Farber Cancer InstituteDepartment of Data Science, Dana-Farber Cancer InstituteCenter for Functional Cancer Epigenetics, Dana-Farber Cancer InstituteCenter for Functional Cancer Epigenetics, Dana-Farber Cancer InstituteDepartment of Data Science, Dana-Farber Cancer InstituteDepartment of Data Science, Dana-Farber Cancer InstituteDepartment of Data Science, Dana-Farber Cancer InstituteDepartment of Data Science, Dana-Farber Cancer InstituteDepartment of Data Science, Dana-Farber Cancer InstituteUniversity of Texas Southwestern Medical SchoolDepartment of Data Science, Dana-Farber Cancer InstituteCenter for Functional Cancer Epigenetics, Dana-Farber Cancer InstituteDepartment of Medical Oncology, Dana-Farber Cancer InstituteCenter for Functional Cancer Epigenetics, Dana-Farber Cancer InstituteDepartment of Data Science, Dana-Farber Cancer InstituteAbstract 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.http://link.springer.com/article/10.1186/s13059-020-02166-1Clonal tracingImmune checkpoint blockadeHeterogeneityTumor microenvironmentMathematical modeling |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Shengqing Stan Gu Xiaoqing Wang Xihao Hu Peng Jiang Ziyi Li Nicole Traugh Xia Bu Qin Tang Chenfei Wang Zexian Zeng Jingxin Fu Cliff Meyer Yi Zhang Paloma Cejas Klothilda Lim Jin Wang Wubing Zhang Collin Tokheim Avinash Das Sahu Xiaofang Xing Benjamin Kroger Zhangyi Ouyang Henry Long Gordon J. Freeman Myles Brown X. Shirley Liu |
spellingShingle |
Shengqing Stan Gu Xiaoqing Wang Xihao Hu Peng Jiang Ziyi Li Nicole Traugh Xia Bu Qin Tang Chenfei Wang Zexian Zeng Jingxin Fu Cliff Meyer Yi Zhang Paloma Cejas Klothilda Lim Jin Wang Wubing Zhang Collin Tokheim Avinash Das Sahu Xiaofang Xing Benjamin Kroger Zhangyi Ouyang Henry Long Gordon J. Freeman Myles Brown X. Shirley Liu Clonal tracing reveals diverse patterns of response to immune checkpoint blockade Genome Biology Clonal tracing Immune checkpoint blockade Heterogeneity Tumor microenvironment Mathematical modeling |
author_facet |
Shengqing Stan Gu Xiaoqing Wang Xihao Hu Peng Jiang Ziyi Li Nicole Traugh Xia Bu Qin Tang Chenfei Wang Zexian Zeng Jingxin Fu Cliff Meyer Yi Zhang Paloma Cejas Klothilda Lim Jin Wang Wubing Zhang Collin Tokheim Avinash Das Sahu Xiaofang Xing Benjamin Kroger Zhangyi Ouyang Henry Long Gordon J. Freeman Myles Brown X. Shirley Liu |
author_sort |
Shengqing Stan Gu |
title |
Clonal tracing reveals diverse patterns of response to immune checkpoint blockade |
title_short |
Clonal tracing reveals diverse patterns of response to immune checkpoint blockade |
title_full |
Clonal tracing reveals diverse patterns of response to immune checkpoint blockade |
title_fullStr |
Clonal tracing reveals diverse patterns of response to immune checkpoint blockade |
title_full_unstemmed |
Clonal tracing reveals diverse patterns of response to immune checkpoint blockade |
title_sort |
clonal tracing reveals diverse patterns of response to immune checkpoint blockade |
publisher |
BMC |
series |
Genome Biology |
issn |
1474-760X |
publishDate |
2020-10-01 |
description |
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. |
topic |
Clonal tracing Immune checkpoint blockade Heterogeneity Tumor microenvironment Mathematical modeling |
url |
http://link.springer.com/article/10.1186/s13059-020-02166-1 |
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