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9p21 loss confers a cold tumor immune microenvironment and primary resistance to immune checkpoint therapy
Guangchun Han1, Guoliang Yang2, Dapeng Hao1
1Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Abstract:
Immune checkpoint therapy (ICT) provides substantial clinical benefits to cancer patients, but a large proportion of cancers do not respond to ICT. To date, the genomic underpinnings of primary resistance to ICT remain elusive. Here, we performed immunogenomic analysis of data from TCGA and clinical trials of anti-PD-1/PD-L1 therapy, with a particular focus on homozygous deletion of 9p21.3 (9p21 loss), one of the most frequent genomic defects occurring in ~13% of all cancers. We demonstrate that 9p21 loss confers "cold" tumor-immune phenotypes, characterized by reduced abundance of tumor-infiltrating leukocytes (TILs), particularly, T/B/NK cells, altered spatial TILs patterns, diminished immune cell trafficking/activation, decreased rate of PD-L1 positivity, along with activation of immunosuppressive signaling. Notably, patients with 9p21 loss exhibited significantly lower response rates to ICT and worse outcomes, which were corroborated in eight ICT trials of >1,000 patients. Further, 9p21 loss synergizes with PD-L1/TMB for patient stratification. A "response score" was derived by incorporating 9p21 loss, PD-L1 expression and TMB levels in pre-treatment tumors, which outperforms PD-L1, TMB, and their combination in identifying patients with high likelihood of achieving sustained response from otherwise non-responders. Moreover, we describe potential druggable targets in 9p21-loss tumors, which could be exploited to design rational therapeutic interventions.
Insights
Genomic defects like 9p21 loss create "cold" tumors resistant to immune checkpoint therapy (ICT). This finding helps identify non-responders and suggests new therapeutic strategies for cancer treatment.
Area of Science:
- Oncology
- Immunology
- Genomics
Background:
- Immune checkpoint therapy (ICT) offers significant benefits but faces primary resistance in many cancers.
- The genomic basis for this resistance is not well understood.
- 9p21 loss is a frequent genomic alteration in ~13% of cancers.
Purpose of the Study:
- To investigate the genomic underpinnings of primary resistance to ICT.
- To focus on the role of homozygous deletion of 9p21.3 (9p21 loss) in ICT resistance.
- To develop a predictive model for ICT response.
Main Methods:
- Immunogenomic analysis of TCGA and anti-PD-1/PD-L1 therapy clinical trial data.
- Analysis of tumor-infiltrating leukocytes (TILs), immune cell trafficking, PD-L1 expression, and immunosuppressive signaling in relation to 9p21 loss.
- Development and validation of a predictive response score incorporating 9p21 loss, PD-L1 expression, and tumor mutational burden (TMB).
Main Results:
- 9p21 loss is associated with "cold" tumor-immune phenotypes, including reduced TILs, altered immune cell patterns, and decreased PD-L1 positivity.
- Patients with 9p21 loss showed significantly lower response rates and worse outcomes to ICT.
- A novel "response score" combining 9p21 loss, PD-L1, and TMB outperformed individual markers in predicting sustained ICT response.
Conclusions:
- 9p21 loss is a key genomic driver of primary resistance to ICT.
- The developed response score can improve patient stratification for ICT.
- Targeting 9p21-loss tumors may offer new therapeutic avenues for non-responders.
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