More Like this

1. Toward understanding cancer stem cell heterogeneity in the tumor microenvironment

   https://doi.org/10.1073/pnas.1815345116  

   Bocci, Federico ; Gearhart-Serna, Larisa ; Boareto, Marcelo ; Ribeiro, Mariana ; Ben-Jacob, Eshel ; Devi, Gayathri R. ; Levine, Herbert ; Onuchic, José Nelson ; Jolly, Mohit Kumar ( December 2018 , Proceedings of the National Academy of Sciences)

   The epithelial–mesenchymal transition (EMT) and cancer stem cell (CSC) formation are two paramount processes driving tumor progression, therapy resistance, and cancer metastasis. Recent experiments show that cells with varying EMT and CSC phenotypes are spatially segregated in the primary tumor. The underlying mechanisms generating such spatiotemporal dynamics in the tumor microenvironment, however, remain largely unexplored. Here, we show through a mechanism-based dynamical model that the diffusion of EMT-inducing signals such as TGF-β, together with noncell autonomous control of EMT and CSC decision making via the Notch signaling pathway, can explain experimentally observed disparate localization of subsets of CSCs with varying EMT phenotypes in the tumor. Our simulations show that the more mesenchymal CSCs lie at the invasive edge, while the hybrid epithelial/mesenchymal (E/M) CSCs reside in the tumor interior. Further, motivated by the role of Notch-Jagged signaling in mediating EMT and stemness, we investigated the microenvironmental factors that promote Notch-Jagged signaling. We show that many inflammatory cytokines such as IL-6 that can promote Notch-Jagged signaling can (i) stabilize a hybrid E/M phenotype, (ii) increase the likelihood of spatial proximity of hybrid E/M cells, and (iii) expand the fraction of CSCs. To validate the predicted connection between Notch-Jagged signaling and stemness, we knocked down JAG1 in hybrid E/M SUM149 human breast cancer cells in vitro. JAG1 knockdown significantly restricted tumor organoid formation, confirming the key role that Notch-Jagged signaling can play in tumor progression. Together, our integrated computational–experimental framework reveals the underlying principles of spatiotemporal dynamics of EMT and CSCs.

    

   more » « less
2. Biofabrication of 3D breast cancer models for dissecting the cytotoxic response of human T cells expressing engineered MAIT cell receptors

   https://doi.org/10.1088/1758-5090/ac925a  

   Dey, Madhuri ; Kim, Myong Hwan ; Nagamine, Momoka ; Karhan, Ece ; Kozhaya, Lina ; Dogan, Mikail ; Unutmaz, Derya ; Ozbolat, Ibrahim T ( September 2022 , Biofabrication)

   Abstract Immunotherapy has revolutionized cancer treatment with the advent of advanced cell engineering techniques aimed at targeted therapy with reduced systemic toxicity. However, understanding the underlying immune–cancer interactions require development of advanced three-dimensional (3D) models of human tissues. In this study, we fabricated 3D tumor models with increasing complexity to study the cytotoxic responses of CD8 + T cells, genetically engineered to express mucosal-associated invariant T (MAIT) cell receptors, towards MDA-MB-231 breast cancer cells. Homotypic MDA-MB-231 and heterotypic MDA-MB-231/human dermal fibroblast tumor spheroids were primed with precursor MAIT cell ligand 5-amino-6-D-ribitylaminouracil (5-ARU). Engineered T cells effectively eliminated tumors after a 3 d culture period, demonstrating that the engineered T cell receptor recognized major histocompatibility complex class I-related (MR1) protein expressing tumor cells in the presence of 5-ARU. Tumor cell killing efficiency of engineered T cells were also assessed by encapsulating these cells in fibrin, mimicking a tumor extracellular matrix microenvironment. Expression of proinflammatory cytokines such as interferon gamma, interleukin-13, CCL-3 indicated immune cell activation in all tumor models, post immunotherapy. Further, in corroborating the cytotoxic activity, we found that granzymes A and B were also upregulated, in homotypic as well as heterotypic tumors. Finally, a 3D bioprinted tumor model was employed to study the effect of localization of T cells with respect to tumors. T cells bioprinted proximal to the tumor had reduced invasion index and increased cytokine secretion, which indicated a paracrine mode of immune–cancer interaction. Development of 3D tumor-T cell platforms may enable studying the complex immune–cancer interactions and engineering MAIT cells for cell-based cancer immunotherapies. 

   more » « less
3. Targeting the Interplay between Epithelial-to-Mesenchymal-Transition and the Immune System for Effective Immunotherapy

   https://doi.org/10.3390/cancers11050714  

   Soundararajan, Rama ; Fradette, Jared ; Konen, Jessica ; Moulder, Stacy ; Zhang, Xiang ; Gibbons, Don ; Varadarajan, Navin ; Wistuba, Ignacio ; Tripathy, Debasish ; Bernatchez, Chantale ; et al ( May 2019 , Cancers)

   Over the last decade, both early diagnosis and targeted therapy have improved the survival rates of many cancer patients. Most recently, immunotherapy has revolutionized the treatment options for cancers such as melanoma. Unfortunately, a significant portion of cancers (including lung and breast cancers) do not respond to immunotherapy, and many of them develop resistance to chemotherapy. Molecular characterization of non-responsive cancers suggest that an embryonic program known as epithelial-mesenchymal transition (EMT), which is mostly latent in adults, can be activated under selective pressures, rendering these cancers resistant to chemo- and immunotherapies. EMT can also drive tumor metastases, which in turn also suppress the cancer-fighting activity of cytotoxic T cells that traffic into the tumor, causing immunotherapy to fail. In this review, we compare and contrast immunotherapy treatment options of non-small cell lung cancer (NSCLC) and triple negative breast cancer (TNBC). We discuss why, despite breakthrough progress in immunotherapy, attaining predictable outcomes in the clinic is mostly an unsolved problem for these tumors. Although these two cancer types appear different based upon their tissues of origin and molecular classification, gene expression indicate that they possess many similarities. Patient tumors exhibit activation of EMT, and resulting stem cell properties in both these cancer types associate with metastasis and resistance to existing cancer therapies. In addition, the EMT transition in both these cancers plays a crucial role in immunosuppression, which exacerbates treatment resistance. To improve cancer-related survival we need to understand and circumvent, the mechanisms through which these tumors become therapy resistant. In this review, we discuss new information and complementary perspectives to inform combination treatment strategies to expand and improve the anti-tumor responses of currently available clinical immune checkpoint inhibitors. 

   more » « less
4. Assay‐agnostic spatial profiling detects tumor microenvironment signatures: new diagnostic insights for triple‐negative breast cancer

   https://doi.org/10.1002/1878-0261.13515  

   Ziegler, Colleen ; Mir, Alain ; Anandakrishnan, Sangeetha ; Martin, Patrick ; Contreras, Elma ; Slemons, Isaiah ; Witkowski, Barbara ; DeSilva, Chris ; Farmer, Andrew ; Vranic, Semir ; et al ( September 2023 , Molecular Oncology)

   The role of the tumor microenvironment (TME) in immuno‐oncology has driven demand for technologies that deliverin situ, or spatial, molecular information. Compartmentalized heterogeneity that traditional methods miss is becoming key to predicting both acquired drug resistance to targeted therapies and patient response to immunotherapy. Here, we describe a novel method for assay‐agnostic spatial profiling and demonstrate its ability to detect immune microenvironment signatures in breast cancer patients that are unresolved by the immunohistochemical (IHC) assessment of programmed cell death ligand‐1 (PD‐L1) on immune cells, which represents the only FDA microenvironment‐based companion diagnostic test that has been approved for triple‐negative breast cancer (TNBC). Two distinct physiological states were found that are uncorrelated to tumor mutational burden (TMB), microsatellite instability (MSI),PD‐L1expression, and intrinsic cancer subtypes.

    

   more » « less
5. Integrating genome-wide CRISPR immune screen with multi-omic clinical data reveals distinct classes of tumor intrinsic immune regulators

   https://doi.org/10.1136/jitc-2020-001819  

   Hou, Jiakai ; Wang, Yunfei ; Shi, Leilei ; Chen, Yuan ; Xu, Chunyu ; Saeedi, Arash ; Pan, Ke ; Bohat, Ritu ; Egan, Nicholas A. ; McKenzie, Jodi A. ; et al ( February 2021 , Journal for ImmunoTherapy of Cancer)

   null (Ed.)

   Background Despite approval of immunotherapy for a wide range of cancers, the majority of patients fail to respond to immunotherapy or relapse following initial response. These failures may be attributed to immunosuppressive mechanisms co-opted by tumor cells. However, it is challenging to use conventional methods to systematically evaluate the potential of tumor intrinsic factors to act as immune regulators in patients with cancer. Methods To identify immunosuppressive mechanisms in non-responders to cancer immunotherapy in an unbiased manner, we performed genome-wide CRISPR immune screens and integrated our results with multi-omics clinical data to evaluate the role of tumor intrinsic factors in regulating two rate-limiting steps of cancer immunotherapy, namely, T cell tumor infiltration and T cell-mediated tumor killing. Results Our studies revealed two distinct types of immune resistance regulators and demonstrated their potential as therapeutic targets to improve the efficacy of immunotherapy. Among them, PRMT1 and RIPK1 were identified as a dual immune resistance regulator and a cytotoxicity resistance regulator, respectively. Although the magnitude varied between different types of immunotherapy, genetically targeting PRMT1 and RIPK1 sensitized tumors to T-cell killing and anti-PD-1/OX40 treatment. Interestingly, a RIPK1-specific inhibitor enhanced the antitumor activity of T cell-based and anti-OX40 therapy, despite limited impact on T cell tumor infiltration. Conclusions Collectively, the data provide a rich resource of novel targets for rational immuno-oncology combinations. 

   more » « less