Mismatch repair deficiency is not sufficient to increase tumor immunogenicity
Westcott, P. M. K.; Muyas, F.; Smith, O.; Hauck, H.; Sacks, N. J.; Ely, Z. A.; Jaeger, A. M.; Rideout, W. M.; Bhutkar, A.; Zhang, D.; Beytagh, M. C.; Canner, D. A.; Bronson, R. T.; Naranjo, S.; Jin, A.; Patten, J. J.; Cruz, A. M.; Cortes-Ciriano, I.; Jacks, T.
Show abstract
DNA mismatch repair deficiency (MMRd) in human cancer is associated with high tumor mutational burden (TMB), frameshift mutation-derived neoantigens, increased T cell infiltration, and remarkable responsiveness to immune checkpoint blockade (ICB) therapy. Nevertheless, about half of MMRd tumors do not respond to ICB for unclear reasons. While tumor cell line transplant models of MMRd have reinforced the importance of TMB in immune response, critical questions remain regarding the role of immunosurveillance in the evolution of MMRd tumors induced in vivo. Here, we developed autochthonous mouse models of lung and colon cancer with highly efficient ablation of MMR genes via in vivo CRISPR/Cas9 targeting. Surprisingly, MMRd in these models did not result in increased immunogenicity or response to ICB. Mechanistically, we showed this lack of immunogenicity to be driven by profound intratumoral heterogeneity (ITH). Studies in animals depleted of T cells further demonstrated that immunosurveillance in MMRd tumors has no impact on TMB but shapes the clonal architecture of neoantigens by exacerbating ITH. These results provide important context for understanding immune evasion in cancers with high TMB and have major implications for therapies aimed at increasing TMB.
Matching journals
The top 4 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- In vivo CRISPR screens reveal Serpinb9 and Adam2 as regulators of immune therapy response in lung cancer 97%
- Combinatorial immunotherapies overcome MYC-driven immune evasion 97%
- Desmoplastic stroma restricts T cell extravasation and mediates immune exclusion and immunosuppression in solid tumors 96%
Similar papers in this journal
Similar papers in this journal
Similar papers in this journal
- B3GALT6 Promotes Dormant Breast Cancer Cell Survival and Recurrence by Enabling Heparan Sulfate-Mediated FGF Signaling 96%
- Single-cell lineage and transcriptome reconstruction of metastatic cancer reveals selection of aggressive hybrid EMT states 96%
- An mRNA-encoded, long-lasting Interleukin-2 restores CD8+ T cell neoantigen immunity in MHC class I-deficient cancers 96%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.