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

Baldominos, Pilar; Barbera-Mourelle, Alex; Barreiro, Olga; Huang, Yhu‐Chering; Wight, Andrew; Cho, Jae-Won; Zhao, Xi; Estivill, Guillem; Adam, Isam; Sánchez, Xavier; McCarthy, Shannon E.; Schaller, Julien; Khan, Zara; Ruzo, Albert; Pastorello, Ricardo; Richardson, Edward T.; Dillon, Deborah; Montero-Llopis, Paula; Barroso‐Sousa, Romualdo; Forman, Juliet; Shukla, Sachet A.; Tolaney, Sara M.; Mittendorf, Elizabeth A.; Andrian, Ulrich H. von; Wucherpfennig, Kai W.; Hemberg, Martin; Agudo, Judith

doi:10.1016/j.cell.2022.03.033

Cited by 135 publications

(104 citation statements)

References 57 publications

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“…In this regard, there is overwhelming evidence in literature demonstrating that cancer cells with deep intrinsic resistance, such as that modeled in our system, have several adaptive traits, such as high EMT, that enable them to evade immunity during progression and at the time immune checkpoint therapies are typically offered [29,30]. A recent study has shown that quiescent cancer cells play an important role in resisting T-cell attack in TNBC [31]. Therefore, a good way to improve response to immune therapies would be through therapeutic targeting of deep intrinsic resistance; a cell culture approach such as ours could possibly help in this task.…”

Section: Discussionmentioning

confidence: 94%

Sensitization of resistant cells with a BET bromodomain inhibitor in a cell culture model of deep intrinsic resistance in breast cancer

Singh

Sarli

Milligan

et al. 2022

Preprint

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Background: Cell culture models of cancer typically favor proliferative but therapy-sensitive cells because body-like selection pressures are absent. To address this limitation of cell culture, we previously described a function-based selection strategy to model deep intrinsic resistance in cultures of triple-negative breast cancer cells. To determine the validity of this approach in identifying noncytotoxic drugs that could inhibit the relapse of poor-prognosis minimal residual disease in breast cancer, we used our novel cell culture model to evaluate a well-known BET bromodomain inhibitor, JQ1, which modulates cancer epigenome. Methods: We treated highly metabolically adaptable (SUM149-MA) cells and their control parental SUM149-Luc cell line with JQ1 for long periods to determine its efficacy at inhibiting resistant cells. To measure JQ1-mediated sensitization of resistant cancer cells, we first eradicated approximately 99% of relatively chemotherapy-sensitive cancer cells in culture dishes by long treatments with doxorubicin or paclitaxel, and then analyzed the remaining resistant cells for survival and growth into colonies. Our methods were designed to reveal resistant cancer cells while minimizing the contribution of the vast majority of nonresistant cells that simply proliferate in cell culture. We also performed Western blotting to determine whether JQ1 treatment affected PD-L1 protein levels in cancer cells. Results: After 20 days of treatment with 1-2 µM JQ1, which killed a majority of cells in the parental cell line, a large number of SUM149-MA cells survived, consistent with their pan-resistant nature. Interestingly, though, the JQ1 treatment sensitized resistant cancer cells in both the SUM149-MA and SUM149-Luc cell lines to subsequent treatment with doxorubicin and paclitaxel. In addition, combination, rather than sequential, treatment with JQ1 and doxorubicin was also effective in overcoming resistance. Notably, JQ1-treated cancer cells also had significantly lower levels of PD-L1 protein than did untreated cells. Conclusions: Our results suggest that the noncytotoxic drug JQ1 could inhibit the growth of resistant breast cancer cells at the minimal residual disease stage, prior to relapse. Because it can also reduce PD-L1 protein levels, JQ1 may reduce tumor-mediated immune suppression and improve response to immune therapy targeting PD-L1. In all, our results support the validity of a cell culture-based approach for modeling a cancer adaptability phenotype, namely the opportunistic switching of cancer cells between quiescence and proliferation.

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Section: Discussionmentioning

confidence: 94%

Sensitization of resistant cells with a BET bromodomain inhibitor in a cell culture model of deep intrinsic resistance in breast cancer

Singh

Sarli

Milligan

et al. 2022

Preprint

View full text Add to dashboard Cite

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“…Thus, local conditions for the activity of immune effector cells can be very different within the tumor core, invasive margin, tumor stroma, or early metastatic sites. This can allow survival of residual disease in particular regions of the malignant tumor, even with potentially high effectiveness of the anticancer response or immunotherapy [22]. For a very long time, it While seemingly random, the spatial architecture of TME is in fact a crucial element for the immune evasion [18].…”

Section: The Role Of Tme In Tumor Immune Evasionmentioning

confidence: 99%

Perspectives for 3D-Bioprinting in Modeling of Tumor Immune Evasion

Staros

Michalak

Rusinek

et al. 2022

Cancers

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In a living organism, cancer cells function in a specific microenvironment, where they exchange numerous physical and biochemical cues with other cells and the surrounding extracellular matrix (ECM). Immune evasion is a clinically relevant phenomenon, in which cancer cells are able to direct this interchange of signals against the immune effector cells and to generate an immunosuppressive environment favoring their own survival. A proper understanding of this phenomenon is substantial for generating more successful anticancer therapies. However, classical cell culture systems are unable to sufficiently recapture the dynamic nature and complexity of the tumor microenvironment (TME) to be of satisfactory use for comprehensive studies on mechanisms of tumor immune evasion. In turn, 3D-bioprinting is a rapidly evolving manufacture technique, in which it is possible to generate finely detailed structures comprised of multiple cell types and biomaterials serving as ECM-analogues. In this review, we focus on currently used 3D-bioprinting techniques, their applications in the TME research, and potential uses of 3D-bioprinting in modeling of tumor immune evasion and response to immunotherapies.

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“…Defective DCs inside clusters of quiescent cancer cells can also prompt hypoxia-induced programs. Depending on where they were located inside the tumor, DCs and quiescent cancer cells (QCCs) act as immunotherapy-resistant reservoirs by directing a local immunosuppressive environment that is hypoxic and inhibits T cell activity [ 77 ].…”

Section: Tumor-induced Hypoxic Immunosuppressionmentioning

confidence: 99%

Tumor-Infiltrating Dendritic Cells: Decisive Roles in Cancer Immunosurveillance, Immunoediting, and Tumor T Cell Tolerance

Katopodi

Petanidis

Charalampidis

et al. 2022

Cells

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The tumor microenvironment plays a key role in progression of tumorigenesis, tumor progression, and metastasis. Accumulating data reveal that dendritic cells (DCs) appear to play a key role in the development and progression of metastatic neoplasia by driving immune system dysfunction and establishing immunosuppression, which is vital for tumor evasion of host immune response. Consequently, in this review, we will discuss the function of tumor-infiltrating DCs in immune cell signaling pathways that lead to treatment resistance, tumor recurrence, and immunosuppression. We will also review DC metabolism, differentiation, and plasticity, which are essential for metastasis and the development of lung tumors. Furthermore, we will take into account the interaction between myeloid cells and DCs in tumor-related immunosuppression. We will specifically look into the molecular immune-related mechanisms in the tumor microenvironment that result in reduced drug sensitivity and tumor relapse, as well as methods for combating drug resistance and focusing on immunosuppressive tumor networks. DCs play a crucial role in modulating the immune response. Especially, as cancer progresses, DCs may switch from playing an immunostimulatory to an inhibitory role. This article’s main emphasis is on tumor-infiltrating DCs. We address how they affect tumor growth and expansion, and we highlight innovative approaches for therapeutic modulation of these immunosuppressive DCs which is necessary for future personalized therapeutic approaches.

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

Cited by 135 publications

References 57 publications

Sensitization of resistant cells with a BET bromodomain inhibitor in a cell culture model of deep intrinsic resistance in breast cancer

Sensitization of resistant cells with a BET bromodomain inhibitor in a cell culture model of deep intrinsic resistance in breast cancer

Perspectives for 3D-Bioprinting in Modeling of Tumor Immune Evasion

Tumor-Infiltrating Dendritic Cells: Decisive Roles in Cancer Immunosurveillance, Immunoediting, and Tumor T Cell Tolerance

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