Abstract
Cancer cells that express antigen but are T cell–resistant are found to be principally quiescent.
Major Finding: Cancer cells that express antigen but are T cell–resistant are found to be principally quiescent.
Concept: These cells form a niche of immunosuppressive fibroblasts, dysfunctional dendritic cells, and exhausted T cells.
Impact: This work suggests elimination of this cell population for successful use of immunotherapy in breast cancer.
Immune checkpoint blockade therapy in combination with chemotherapy has shown improvement to progression-free survival in patients with PD-L1–positive triple-negative breast cancer (TNBC); however, only a fraction of these patients will benefit from immunotherapy. The immunosuppressive tumor microenvironment (TME) has been shown to play a role in immunotherapy resistance, with ongoing efforts focusing on identification of resistance drivers in the TME. Baldominos and colleagues sought to address this issue of cancer cell resistance to T cell–mediated cell killing by using GFP as a visible cancer cell antigen along with GFP-specific T cells and showed that most GFP+ TNBC cells were killed by the GFP-specific T cells. However, those that survived formed clusters that exhibited partial T-cell exclusion, downregulation of proliferation genes, and a lack of movement through the cell cycle. Profiling of these quiescent cancer cells (QCC) showed their resistance to T-cell killing as well as their superior ability to regrow tumors and suggested their greater tumor initiation potential as compared to their proliferating counterparts. Immunostaining further revealed poor immune infiltration in these QCC clusters compared to areas containing cycling cells, and use of the approach termed photoconversion of areas to dissect microenvironments (PADME-seq), which allows profiling of infiltrating cells within the same tumor mass, showed more immune-suppressive fibroblasts in the QCC niche as well as exhaustion of the T cells that did enter. Moreover, this T-cell dysfunction was attributed to a reduction in innate immunity and immune-response pathways in dendritic cells present within the QCC niche, suggesting their inability to recruit and activate T cells. Thus, in summary, this work reveals quiescence as a potential driver of immune exclusion and resistance to T-cell attack and suggests the targeting of this cell population could improve patient response to immunotherapy and prevent recurrence in TNBC.
Note:Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.
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