MHC-I downregulation is associated with immune-evasion in breast cancers with heterogeneous activation of epithelial-mesenchymal plasticity
- 1Cornell University
Abstract
Cancer cell-intrinsic epithelial-mesenchymal plasticity (EMP) drives carcinoma progression through increased intratumoral heterogeneity and an immunosuppressive tumor microenvironment (TME). Specifically, EMP activation in murine mammary carcinomas results in exclusion of CD8+ T-cells and recruitment of immunosuppressive M2-like macrophages, resulting in resistance to anti-CTLA-4 immune checkpoint blockade (ICB) therapy. Notably, mixed E-qM tumors in which only 10% of cancer cells have activated EMP are resistant anti-CTLA-4 immune checkpoint blockade (ICB) therapy. This suggests that minority fractions of qM cancer cells could, in theory, exert immunosuppressive effects on surrounding E cancer and immune cells to shield the entire heterogeneous tumor against immune attack. However, this has not yet been demonstrated. Here, we use spatial transcriptomic profiling to demonstrate that mixed E-qM tumors assemble immunosuppressive cellular niches. Furthermore, E cancer cells within mixed E-qM tumors experience long-term MHC-I downregulation leading to resistance to elimination by CD8+ T-cells. This is associated with the exclusion of T-cells from the tumor core and a dysfunctional phenotype in the remaining CD8+ T-cells. qM cancer cells recruit immunosuppressive M2-like macrophages to mixed tumors, which further downregulates E cancer cell-intrinsic MHC-I levels. Finally, we demonstrate that human triple-negative breast cancers with increased EMP activation exclude T-cells from the tumor core. Together, these findings reveal that qM cancer cells modulate the immune infiltrate of mixed tumors, promoting MHC-I downregulation and evasion of immunological control by CD8+ T-cells.
Related
- Methylation-associated downregulation of CRABP1 marks an aggressive malignant epithelial cell state in thyroid carcinoma.
- Integrative Multi-Omics Reveals TSPAN13 as a Candidate Epithelial–Mesenchymal Transition-Associated Regulator in Prostate Cancer
- Keratin 17 Defines an Epithelial-Mesenchymal Transition-Associated Migratory Cell State in Pancreatic Ductal Adenocarcinoma
- Catenin Alpha-Like 1 (CTNNAL1) Modulates Cancer Stem Cell-Associated Properties and Epithelial-Mesenchymal Transition (EMT)-Associated Phenotypes in MDA-MB-231 Breast Cancer Cells.
- Human Papillomavirus (HPV) Infection-Associated Epithelial-to-Mesenchymal Transition: Implication in Tumorigenesis and Pathogenesis of HPV-Positive Cancers
BibTeX
@misc{bakhle2026mhci,
title = {{MHC-I downregulation is associated with immune-evasion in breast cancers with heterogeneous activation of epithelial-mesenchymal plasticity}},
author = {K. M. Bakhle and A. Stephanou and S. Sahoo and I. Ntekas and K. Priebe and M. Rahman and R. Puri and S. Butler and P. Schweitzer and S. Chandraganti and M. K. Jolly and I. De Vlaminck and P. Sethupathy and A. Dongre},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.17.759751},
url = {https://www.biorxiv.org/content/10.64898/2026.10.17.759751v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - MHC-I downregulation is associated with immune-evasion in breast cancers with heterogeneous activation of epithelial-mesenchymal plasticity
AU - K. M. Bakhle
AU - A. Stephanou
AU - S. Sahoo
AU - I. Ntekas
AU - K. Priebe
AU - M. Rahman
AU - R. Puri
AU - S. Butler
AU - P. Schweitzer
AU - S. Chandraganti
AU - M. K. Jolly
AU - I. De Vlaminck
AU - P. Sethupathy
AU - A. Dongre
PY - 2026
DA - 2026/10/17
PB - bioRxiv
DO - 10.64898/2026.10.17.759751
UR - https://www.biorxiv.org/content/10.64898/2026.10.17.759751v1
AB - Cancer cell-intrinsic epithelial-mesenchymal plasticity (EMP) drives carcinoma progression through increased intratumoral heterogeneity and an immunosuppressive tumor microenvironment (TME). Specifically, EMP activation in murine mammary carcinomas results in exclusion of CD8+ T-cells and recruitment of immunosuppressive M2-like macrophages, resulting in resistance to anti-CTLA-4 immune checkpoint blockade (ICB) therapy. Notably, mixed E-qM tumors in which only 10% of cancer cells have activated EMP are resistant anti-CTLA-4 immune checkpoint blockade (ICB) therapy. This suggests that minority fractions of qM cancer cells could, in theory, exert immunosuppressive effects on surrounding E cancer and immune cells to shield the entire heterogeneous tumor against immune attack. However, this has not yet been demonstrated. Here, we use spatial transcriptomic profiling to demonstrate that mixed E-qM tumors assemble immunosuppressive cellular niches. Furthermore, E cancer cells within mixed E-qM tumors experience long-term MHC-I downregulation leading to resistance to elimination by CD8+ T-cells. This is associated with the exclusion of T-cells from the tumor core and a dysfunctional phenotype in the remaining CD8+ T-cells. qM cancer cells recruit immunosuppressive M2-like macrophages to mixed tumors, which further downregulates E cancer cell-intrinsic MHC-I levels. Finally, we demonstrate that human triple-negative breast cancers with increased EMP activation exclude T-cells from the tumor core. Together, these findings reveal that qM cancer cells modulate the immune infiltrate of mixed tumors, promoting MHC-I downregulation and evasion of immunological control by CD8+ T-cells.
ER -