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Updated: Jul 16, 2025
Tailoring In Vivo Cytotoxicity Assays to Study Immunodominance in Tumor-specific CD8+ T Cell Responses
Published on: May 6, 2019
Mismatch repair deficiency is not sufficient to elicit tumor immunogenicity
Peter M K Westcott1,2, Francesc Muyas3, Haley Hauck4
1David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA. westcott@cshl.edu.
Abstract:
DNA mismatch repair deficiency (MMRd) is associated with a high tumor mutational burden (TMB) and sensitivity to immune checkpoint blockade (ICB) therapy. Nevertheless, most MMRd tumors do not durably respond to ICB and critical questions remain about immunosurveillance and TMB in these tumors. In the present study, we developed autochthonous mouse models of MMRd lung and colon cancer. Surprisingly, these models did not display increased T cell infiltration or ICB response, which we showed to be the result of substantial intratumor heterogeneity of mutations. Furthermore, we found that immunosurveillance shapes the clonal architecture but not the overall burden of neoantigens, and T cell responses against subclonal neoantigens are blunted. Finally, we showed that clonal, but not subclonal, neoantigen burden predicts ICB response in clinical trials of MMRd gastric and colorectal cancer. These results provide important context for understanding immune evasion in cancers with a high TMB and have major implications for therapies aimed at increasing TMB.
Insights
Most DNA mismatch repair deficient (dMMR) tumors resist immune checkpoint blockade (ICB) due to mutation heterogeneity. Clonal neoantigen burden, not subclonal, predicts ICB response in dMMR cancers.
Area of Science:
- Oncology
- Immunology
- Genetics
Background:
- DNA mismatch repair deficiency (dMMR) often leads to high tumor mutational burden (TMB) and sensitivity to immune checkpoint blockade (ICB).
- However, a significant proportion of dMMR tumors exhibit resistance to ICB, highlighting gaps in understanding tumor immunosurveillance and TMB.
- Intratumor heterogeneity and neoantigen presentation are critical factors influencing treatment efficacy.
Purpose of the Study:
- To investigate the mechanisms underlying immune evasion in dMMR cancers despite high TMB.
- To determine the role of immunosurveillance in shaping tumor clonal architecture and neoantigen landscape.
- To identify predictive biomarkers for ICB response in dMMR tumors.
Main Methods:
- Development of autochthonous mouse models for dMMR lung and colon cancer.
- Analysis of T cell infiltration and response to ICB in preclinical models.
- Assessment of intratumor mutation heterogeneity and clonal architecture.
- Evaluation of neoantigen burden (clonal vs. subclonal) and T cell responses.
- Correlation of neoantigen burden with ICB response in clinical trial data of dMMR gastric and colorectal cancer.
Main Results:
- dMMR mouse models unexpectedly showed limited T cell infiltration and ICB response, attributed to significant intratumor mutation heterogeneity.
- Immunosurveillance influenced tumor clonal composition but not the overall neoantigen load.
- T cell responses against subclonal neoantigens were diminished.
- Clonal neoantigen burden, unlike subclonal, emerged as a predictor of ICB response in clinical dMMR cancer cohorts.
Conclusions:
- Intratumor heterogeneity is a key mechanism of immune evasion in dMMR cancers with high TMB.
- Immunosurveillance shapes tumor evolution, but T cell recognition of subclonal neoantigens is impaired.
- Clonal neoantigen burden is a promising biomarker for predicting ICB efficacy in dMMR malignancies.
- Findings have significant implications for optimizing immunotherapies targeting TMB-high cancers.
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