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Updated: Dec 5, 2025
Tumor Transplantation for Assessing the Dynamics of Tumor-Infiltrating CD8+ T Cells in Mice
Published on: June 12, 2021
Clonal tracing reveals diverse patterns of response to immune checkpoint blockade
Shengqing Stan Gu1,2,3, Xiaoqing Wang3,4,5, Xihao Hu1,2,3
1Department of Data Science, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
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.
Insights
Tumors from the same origin show varied responses to immune checkpoint blockade (ICB) therapy. This heterogeneity highlights the need to monitor cancer clones and tumor microenvironments for better treatment strategies.
Area of Science:
- Immunotherapy
- Cancer Biology
- Genomics
Background:
- Immune checkpoint blockade (ICB) therapy offers survival benefits for cancer patients, but response rates remain limited.
- Identifying biomarkers for ICB response and understanding resistance mechanisms in individual tumors is crucial.
- This study investigates whether tumors with identical genetic origins display consistent or varied responses to ICB.
Purpose of the Study:
- To determine the heterogeneity of ICB response in tumors originating from the same clonal populations.
- To identify molecular and cellular drivers of ICB resistance.
- To correlate findings with clinical data from ICB treatment cohorts.
Main Methods:
- Development of a unique mouse model for clonal tracing and mathematical modeling of tumor growth.
- Monitoring of individual cancer clones and bulk tumor response to ICB.
- Analysis of gene expression signatures associated with ICB resistance.
Main Results:
- Tumors from the same clonal origin exhibited heterogeneous responses and diverse patterns to ICB.
- Initial response to ICB was linked to increased immune infiltration and enrichment of pre-existing resistant clones.
- Cancer cell-intrinsic gene expression signatures, including interferon and glucocorticoid response genes, were associated with ICB resistance.
Conclusions:
- The study reveals diverse ICB response patterns even from identical ancestral cancer cells.
- Monitoring clonal evolution and tumor microenvironment dynamics is vital for optimizing ICB therapy and developing combination treatments.
- ICB treatment may enrich for intrinsic resistance signatures, impacting the interpretation of RNA-sequencing data in response-association studies.
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