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Clonal tracing reveals the contribution of both cancer-intrinsic and -extrinsic mechanisms to the heterogeneity of responses to immune checkpoint blockade [RNA-seq_ICB]

ABSTRACT: Although multiple studies have investigated the biomarkers of response to immune checkpoint blockade (ICB), the significance of each biomarker varies across clinical cohorts independent of cancer type. It remains unclear whether primary ICB response and resistance is encoded in the cancer cells (cancer-intrinsic) or driven by the immune microenvironment unique to each host (cancer-extrinsic). To answer this question, we established a unique mouse system that utilizes clonal tracing and mathematical modeling to uncouple the cancer-intrinsic and -extrinsic mechanisms of ICB resistance. We found that tumors with the same clonal constitution show heterogeneous ICB response in different hosts. Primary resistance is associated with the cancer-extrinsic immune microenvironment rather than proliferation of intrinsically ICB-resistant cancer cells. Instead, pre-existing cancer-intrinsic ICB-resistant clones with distinct transcriptional and epigenetic profiles were enriched in responders. We further identified two gene expression signatures associated with cancer-intrinsic resistance, including increased interferon response genes and glucocorticoid response genes. Our findings are supported by experiments in another mouse model and clinical data from multiple ICB treatment cohorts. Our study emphasizes the importance of optimal microenvironment in cancer immunotherapy, and implicates the value of immunotherapy biomarkers that account for both cancer-intrinsic and -extrinsic mechanisms of resistance.

ORGANISM(S): Mus musculus

PROVIDER: GSE139475 | GEO | 2020/07/01

REPOSITORIES: GEO

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Clonal tracing reveals the contribution of both cancer-intrinsic and -extrinsic mechanisms to the heterogeneity of responses to immune checkpoint blockade [RNA-seq]

Project description:Although multiple studies have investigated the biomarkers of response to immune checkpoint blockade (ICB), the significance of each biomarker varies across clinical cohorts independent of cancer type. It remains unclear whether primary ICB response and resistance is encoded in the cancer cells (cancer-intrinsic) or driven by the immune microenvironment unique to each host (cancer-extrinsic). To answer this question, we established a unique mouse system that utilizes clonal tracing and mathematical modeling to uncouple the cancer-intrinsic and -extrinsic mechanisms of ICB resistance. We found that tumors with the same clonal constitution show heterogeneous ICB response in different hosts. Primary resistance is associated with the cancer-extrinsic immune microenvironment rather than proliferation of intrinsically ICB-resistant cancer cells. Instead, pre-existing cancer-intrinsic ICB-resistant clones with distinct transcriptional and epigenetic profiles were enriched in responders. We further identified two gene expression signatures associated with cancer-intrinsic resistance, including increased interferon response genes and glucocorticoid response genes. Our findings are supported by experiments in another mouse model and clinical data from multiple ICB treatment cohorts. Our study emphasizes the importance of optimal microenvironment in cancer immunotherapy, and implicates the value of immunotherapy biomarkers that account for both cancer-intrinsic and -extrinsic mechanisms of resistance.

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Clonal tracing reveals the contribution of both cancer-intrinsic and -extrinsic mechanisms to the heterogeneity of responses to immune checkpoint blockade [ATAC-seq]

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