Quiescent cancer cells resist T cell attack by forming an immunosuppressive niche

[EN] Immunotherapy is a promising treatment for triple-negative breast cancer (TNBC), but patients relapse, highlighting the need to understand the mechanisms of resistance. We discovered that in primary breast cancer, tumor cells that resist T cell attack are quiescent. Quiescent cancer cells (QCCs) form clusters with reduced immune infiltration. They also display superior tumorigenic capacity and higher expression of chemotherapy resistance and stemness genes. We adapted single-cell RNA-sequencing with precise spatial resolution to profile infiltrating cells inside and outside the QCC niche. This transcriptomic analysis revealed hypoxia-induced programs and identified more exhausted T cells, tumor-protective fibroblasts, and dysfunctional dendritic cells inside clusters of QCCs. This uncovered differential phenotypes in infiltrating cells based on their intra-tumor location. Thus, QCCs constitute immunotherapy-resistant reservoirs by orchestrating a local hypoxic immune-suppressive milieu that blocks T cell function. Eliminating QCCs holds the promise to counteract immunotherapy resistance and prevent disease recurrence in TNBC.We thank G. Freeman, K. Polyak, S.K. Dougan (DFCI), M. Haigis (HMS), C. Kim (BCH), and S. McAllister (BWH) for helpful discussions and review of the manuscript. We thank R. Weinberg (MIT) for providing 4T07 and D2A1 cells. We thank P.L. Sulkowski for helping us with hypoxic chamber experiments. We thank the Micron Microscopy Core (HMS) and the Molecular Imaging Core (DFCI) for image acquisition and the Brigham and Women's Hospital Single Cell Core for generation of the scRNA-seq data. P.B. was supported by La Caixa pre-doctoral fellowship (LCF/BQ/AA18/11680040) funded by ``La Caixa'' Foundation (ID 100010434). S.A.S. acknowledges support from the NCI (R50RCA211482). S.M. is funded by the T32 NIH grant (T32CA207021). A.W. is funded by the Claudia Adams Barr program for Innovative Cancer Research. J.-W.C. and M.H. were supported by the Helmsley foundation (126320) and startup funds from the Evergrande Center. J.A. was supported by the Mary Kay Foundation, the Susan G. Komen Career Catalyst award, the Smith Family Awards Program for Excellence in Biomedical Research, the Ludwig Center at Harvard, the Ira Schneider Foundation, and the DF/HCC Breast SPORE: grant 1P50CA168504. Schemes were created with BioRender.comBaldominos, P.; Barbera-Mourelle, A.; Barreiro, O.; Huang, Y.; Wight, A.; Cho, J.; Zhao, X.... (2022). Quiescent cancer cells resist T cell attack by forming an immunosuppressive niche. Cell. 185(10):1694-1708. https://doi.org/10.1016/j.cell.2022.03.033169417081851

Molecular map of chronic lymphocytic leukemia and its impact on outcome

Recent advances in cancer characterization have consistently revealed marked heterogeneity, impeding the completion of integrated molecular and clinical maps for each malignancy. Here, we focus on chronic lymphocytic leukemia (CLL), a B cell neoplasm with variable natural history that is conventionally categorized into two subtypes distinguished by extent of somatic mutations in the heavy-chain variable region of immunoglobulin genes (IGHV). To build the 'CLL map,' we integrated genomic, transcriptomic and epigenomic data from 1,148 patients. We identified 202 candidate genetic drivers of CLL (109 new) and refined the characterization of IGHV subtypes, which revealed distinct genomic landscapes and leukemogenic trajectories. Discovery of new gene expression subtypes further subcategorized this neoplasm and proved to be independent prognostic factors. Clinical outcomes were associated with a combination of genetic, epigenetic and gene expression features, further advancing our prognostic paradigm. Overall, this work reveals fresh insights into CLL oncogenesis and prognostication

Molecular map of chronic lymphocytic leukemia and its impact on outcome

A genomic, transcriptomic and epigenomic analysis of chronic lymphocytic leukemia identifies genetic drivers and molecular subtypes associated with clinical outcomes. Recent advances in cancer characterization have consistently revealed marked heterogeneity, impeding the completion of integrated molecular and clinical maps for each malignancy. Here, we focus on chronic lymphocytic leukemia (CLL), a B cell neoplasm with variable natural history that is conventionally categorized into two subtypes distinguished by extent of somatic mutations in the heavy-chain variable region of immunoglobulin genes (IGHV). To build the 'CLL map,' we integrated genomic, transcriptomic and epigenomic data from 1,148 patients. We identified 202 candidate genetic drivers of CLL (109 new) and refined the characterization of IGHV subtypes, which revealed distinct genomic landscapes and leukemogenic trajectories. Discovery of new gene expression subtypes further subcategorized this neoplasm and proved to be independent prognostic factors. Clinical outcomes were associated with a combination of genetic, epigenetic and gene expression features, further advancing our prognostic paradigm. Overall, this work reveals fresh insights into CLL oncogenesis and prognostication