Principal Investigator: Anushka Dongre

DESCRIPTION (provided by applicant): 

Although immune checkpoint blockade (ICB) therapy has revolutionized cancer treatment by improving survival, most tumor types still remain unresponsive. We have demonstrated that the epithelialmesenchymal transition (EMT), a cell-biological process that facilitates metastasis, also drives resistance of breast tumors to ICB therapies. Specifically, epithelial tumors recruit CD8+ T-cells and are sensitive to anti-CTLA4 ICB therapy, while mesenchymal tumors recruit immune-suppressive Tregs and M2-like macrophages instead and are resistant to the same therapy. Moreover, in mixed tumors comprised of both cancer cell types, a minority fraction of more-mesenchymal cancer cells (10%) can protect their epithelial neighbors (90%) from immune attack. However, the underlying mechanism(s) of such cross-protection remains elusive. Until recently, heterotypic interactions within the tumor microenvironment have been largely studied using high-throughput scRNA-seq and related technologies, which do not preserve the spatial contexture of immune cells or cancer cells within such tumors. Most importantly, the specific application of spatial transcriptomics to study gradients of immune-suppression as they relate to epithelial and mesenchymal cancer cells within heterogeneous breast tumors has never been attempted before. Thus, we plan to utilize our novel, pre-clinical models of heterogeneous breast tumors in conjunction with spatial transcriptomics to better understand how cross-protection in mixed tumors drives resistance to immunotherapy. We propose that immune-suppressive factors released by more-mesenchymal cancer cells alter the immunomodulatory properties of the juxtaposed epithelial carcinoma cells in mixed tumors, thereby shielding them from anti-tumor immunity. Additionally, these factors also act directly on immune cells driving migration into distinct regions within mixed tumors to exert immune-suppressive effects. Our work has direct translational potential, as identifying the mechanism(s) of cross-protection will enable us to interrupt these signaling channels to potentiate the efficacy of ICB therapies for refractory breast tumors.