MHC-I downregulation is associated with immune-evasion in breast cancers with heterogeneous activation of epithelial-mesenchymal plasticity

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. Significance statement Epithelial-mesenchymal plasticity (EMP) drives the formation of an immunosuppressive tumor microenvironment (TME). Notably, EMP activation in just 10% of cancer cells promotes immunosuppression and immunotherapy resistance in heterogeneous murine mammary tumors. However, it was previously unknown how minority fractions of EMP-activated cancer cells act within heterogeneous tumors to cross-protect neighboring cancer cells against immune attack. Here, we show that minority fractions of quasi-mesenchymal cancer cells result in an altered immune infiltrate with fewer T-cells and increased tumor-associated macrophages. Together, these changes to the TME lead to MHC-I downregulation in surrounding epithelial cancer cells, which shields these cells against recognition by cytotoxic CD8+ T-cells. These results reveal a potential mechanism of immune-evasion and immunotherapy resistance in heterogeneous breast tumors.