Oncology
Abstract
MERTK is ectopically expressed and promotes survival in acute lymphoblastic leukemia (ALL) cells and is thus a potential therapeutic target. Here we demonstrate both direct therapeutic effects of MERTK inhibition on leukemia cells and induction of anti-leukemia immunity via suppression of the coinhibitory PD-1 axis. A MERTK-selective tyrosine kinase inhibitor, MRX-2843, mediated therapeutic anti-leukemia effects in immunocompromised mice bearing a MERTK-expressing human leukemia xenograft. In addition, inhibition of host MERTK by genetic deletion (Mertk–/– mice) or treatment with MRX-2843 significantly decreased tumor burden and prolonged survival in immune-competent mice inoculated with a MERTK-negative ALL, suggesting immune-mediated therapeutic activity. In this context, MERTK inhibition led to significant decreases in expression of the coinhibitory ligands PD-L1 and PD-L2 on CD11b+ monocytes/macrophages in the leukemia microenvironment. Furthermore, although T cells do not express MERTK, inhibition of MERTK indirectly decreased PD-1 expression on CD4+ and CD8+ T cells and decreased the incidence of splenic FOXP3+ Tregs at sites of leukemic infiltration, leading to increased T cell activation. These data demonstrate direct and immune-mediated therapeutic activities in response to MERTK inhibition in ALL models and provide validation of a translational agent targeting MERTK for modulation of tumor immunity.
Authors
Alisa B. Lee-Sherick, Kristen M. Jacobsen, Curtis J. Henry, Madeline G. Huey, Rebecca E. Parker, Lauren S. Page, Amanda A. Hill, Xiaodong Wang, Stephen V. Frye, H. Shelton Earp, Craig T. Jordan, Deborah DeRyckere, Douglas K. Graham
Abstract
Glioblastoma (GBM) remains uniformly lethal, and despite a large accumulation of immune cells in the microenvironment, there is limited antitumor immune response. To overcome these challenges, a comprehensive understanding of GBM systemic immune response during disease progression is required. Here, we integrated multiparameter flow cytometry and mass cytometry TOF (CyTOF) analysis of patient blood to determine changes in the immune system among tumor types and over disease progression. Utilizing flow cytometry analysis in a cohort of 259 patients ranging from benign to malignant primary and metastatic brain tumors, we found that GBM patients had a significant elevation in myeloid-derived suppressor cells (MDSCs) in peripheral blood but not immunosuppressive Tregs. In GBM patient tissue, we found that increased MDSC levels in recurrent GBM portended poor prognosis. CyTOF analysis of peripheral blood from newly diagnosed GBM patients revealed that reduced MDSCs over time were accompanied by a concomitant increase in DCs. GBM patients with extended survival also had reduced MDSCs, similar to the levels of low-grade glioma (LGG) patients. Our findings provide a rationale for developing strategies to target MDSCs, which are elevated in GBM patients and predict poor prognosis.
Authors
Tyler J. Alban, Alvaro G. Alvarado, Mia D. Sorensen, Defne Bayik, Josephine Volovetz, Emily Serbinowski, Erin E. Mulkearns-Hubert, Maksim Sinyuk, James S. Hale, Giovana R. Onzi, Mary McGraw, Pengjing Huang, Matthew M. Grabowski, Connor A. Wathen, Manmeet S. Ahluwalia, Tomas Radivoyevitch, Harley I. Kornblum, Bjarne W. Kristensen, Michael A. Vogelbaum, Justin D. Lathia
Abstract
Immune checkpoint blockade has achieved significant therapeutic success for a subset of cancer patients; however, a large portion of cancer patients do not respond. Unresponsive tumors are characterized as being immunologically “cold,” indicating that these tumors lack tumor antigen-specific primed cytotoxic T cells. Sitravatinib is a spectrum-selective tyrosine kinase inhibitor targeting TAM (TYRO3, AXL, MerTK) and split tyrosine-kinase domain–containing receptors (VEGFR and PDGFR families and KIT) plus RET and MET, targets that contribute to the immunosuppressive tumor microenvironment. We report that sitravatinib has potent antitumor activity by targeting the tumor microenvironment, resulting in innate and adaptive immune cell changes that augment immune checkpoint blockade. These results suggest that sitravatinib has the potential to combat resistance to immune checkpoint blockade and expand the number of cancer patients that are responsive to immune therapy.
Authors
Wenting Du, Huocong Huang, Noah Sorrelle, Rolf A. Brekken
Abstract
BACKGROUND. Commercial gene expression assays are guiding clinical decision making in patients with prostate cancer, particularly when considering active surveillance. Given heterogeneity and multifocality of primary prostate cancer, such assays should ideally be robust to the coexistence of unsampled higher grade disease elsewhere in the prostate in order to have clinical utility. Herein, we comprehensively evaluated transcriptomic profiles of primary multifocal prostate cancer to assess robustness to clinically relevant multifocality. METHODS. We designed a comprehensive, multiplexed targeted RNA-sequencing assay capable of assessing multiple transcriptional classes and deriving commercially available prognostic signatures, including the Myriad Prolaris Cell Cycle Progression score, the Oncotype DX Genomic Prostate Score, and the GenomeDX Decipher Genomic Classifier. We applied this assay to a retrospective, multi-institutional cohort of 156 prostate cancer samples. Derived commercial biomarker scores for 120 informative primary prostate cancer samples from 44 cases were determined and compared. RESULTS. Derived expression scores were positively correlated with tumor grade (rS = 0.53–0.73; all P < 0.001), both within the same case and across the entire cohort. In cases of extreme grade-discordant multifocality (co-occurrence of grade group 1 [GG1] and ≥GG4 foci], gene expression scores were significantly lower in low- (GG1) versus high-grade (≥GG4) foci (all P < 0.001). No significant differences in expression scores, however, were observed between GG1 foci from prostates with and without coexisting higher grade cancer (all P > 0.05). CONCLUSIONS. Multifocal, low-grade and high-grade prostate cancer foci exhibit distinct prognostic expression signatures. These findings demonstrate that prognostic RNA expression assays performed on low-grade prostate cancer biopsy tissue may not provide meaningful information on the presence of coexisting unsampled aggressive disease. FUNDING. Prostate Cancer Foundation, National Institutes of Health (U01 CA214170, R01 CA183857, University of Michigan Prostate Specialized Program of Research Excellence [S.P.O.R.E.] P50 CA186786-05, Weill Cornell Medicine S.P.O.R.E. P50 CA211024-01A1), Men of Michigan Prostate Cancer Research Fund, University of Michigan Comprehensive Cancer Center core grant (2-P30-CA-046592-24), A. Alfred Taubman Biomedical Research Institute, and Department of Defense.
Authors
Simpa S. Salami, Daniel H. Hovelson, Jeremy B. Kaplan, Romain Mathieu, Aaron M. Udager, Nicole E. Curci, Matthew Lee, Komal R. Plouffe, Lorena Lazo de la Vega, Martin Susani, Nathalie Rioux-Leclercq, Daniel E. Spratt, Todd M. Morgan, Matthew S. Davenport, Arul M. Chinnaiyan, Joanna Cyrta, Mark A. Rubin, Shahrokh F. Shariat, Scott A. Tomlins, Ganesh S. Palapattu
Abstract
BACKGROUND. Tumor content in circulating cell-free DNA (cfDNA) is a promising biomarker, but longitudinal dynamics of tumor-derived and non–tumor-derived cfDNA through multiple courses of therapy have not been well described. METHODS. CfDNA from 663 plasma samples from 140 patients with castration-resistant prostate cancer (CRPC) was subject to sparse whole genome sequencing. Tumor fraction (TFx) estimated using the computational tool ichorCNA was correlated with clinical features and responses to therapy. RESULTS. TFx associated with the number of bone metastases (median TFx = 0.014 with no bone metastases, 0.047 with 1–3 bone metastases, 0.190 for 4+ bone metastases; P < 0.0001) and with visceral metastases (P < 0.0001). In multivariable analysis, TFx remained associated with metastasis location (P = 0.042); TFx was positively correlated with alkaline phosphatase (P = 0.0227) and negatively correlated with hemoglobin (Hgb) (P < 0.001), but it was not correlated with prostate specific antigen (PSA) (P = 0.75). Tumor-derived and non–tumor-derived cfDNA track together and do not increase with generalized tissue damage from chemotherapy or radiation at the time scales examined. All new treatments that led to ≥30% PSA decline at 6 weeks were associated with TFx decline when baseline TFx was >7%; however, TFx in patients being subsequently maintained on secondary hormonal therapy was quite dynamic. CONCLUSION. TFx correlates with clinical features associated with overall survival in CRPC, and TFx decline is a promising biomarker for initial therapeutic response. TRIAL REGISTRATION. Dana-Farber/Harvard Cancer Center (DF/HCC) protocol no. 18-135. FUNDING. Wong Family Award in Translational Oncology, Dana Farber Cancer Institute Medical Oncology grant, Gerstner Family Foundation, Janssen Pharmaceuticals Inc., and Koch Institute Support (core) grant P30-CA14051 from the National Cancer Institute (NCI).
Authors
Atish D. Choudhury, Lillian Werner, Edoardo Francini, Xiao X. Wei, Gavin Ha, Samuel S. Freeman, Justin Rhoades, Sarah C. Reed, Gregory Gydush, Denisse Rotem, Christopher Lo, Mary-Ellen Taplin, Lauren C. Harshman, Zhenwei Zhang, Edward P. O’Connor, Daniel G. Stover, Heather A. Parsons, Gad Getz, Matthew Meyerson, J. Christopher Love, William C. Hahn, Viktor A. Adalsteinsson
Abstract
Cancer results from the accumulation of genetic mutations in a susceptible cell of origin. We and others have also shown that injury promotes sarcoma development, but how injury cooperates with genetic mutations at the earliest stages of tumor formation is not known. Here, we utilized dual recombinase technology to dissect the complex interplay of the timing of KrasG12D activation, p53 deletion, and muscle injury in sarcomagenesis using a primary mouse model of soft tissue sarcoma. When mutations in oncogenic Kras and p53 are separated by 3 weeks, few sarcomas develop without injury. However, the transformation potential of these tumor-initiating cells can be unmasked by muscle injury. In the absence of Kras mutations, injury of the muscle with global deletion of p53 results in sarcomas with amplification of chromosomal regions encompassing the Met or Yap1 gene. These findings demonstrate a complex interplay between the timing of genetic mutations and perturbations in the tumor microenvironment, which provides insight into the earliest stages of sarcoma development.
Authors
David Van Mater, Eric Xu, Anupama Reddy, Leonor Añó, Mohit Sachdeva, Wesley Huang, Nerissa Williams, Yan Ma, Cassandra Love, Lanie Happ, Sandeep Dave, David G. Kirsch
Abstract
Molecular mechanisms underlying the cancer stroma in metastasis need further exploration. Here, we discovered that cancer-associated fibroblasts (CAFs) produced high levels of IL-33 that acted on tumor-associated macrophages (TAMs), causing them to undergo the M1 to M2 transition. Genomic profiling of metastasis-related genes in the IL-33–stimulated TAMs showed a >200-fold increase of MMP9. Signaling analysis demonstrated the IL-33-ST2-NF-κB-MMP9-laminin pathway that governed tumor stroma–mediated metastasis. In mouse and human fibroblast-rich pancreatic cancers, genetic deletion of IL-33, ST2, or MMP9 markedly blocked metastasis. Pharmacological inhibition of NF-κB and MMP9 also blocked cancer metastasis. Deletion of IL-33, ST2, or MMP9 restored laminin, a key basement membrane component associated with tumor microvessels. Together, our data provide mechanistic insights on the IL-33-NF-κB-MMP9-laminin axis that mediates the CAF-TAM–committed cancer metastasis. Thus, targeting the CAF-TAM-vessel axis provides an outstanding therapeutic opportunity for cancer treatment.
Authors
Patrik Andersson, Yunlong Yang, Kayoko Hosaka, Yin Zhang, Carina Fischer, Harald Braun, Shuzhen Liu, Guohua Yu, Shihai Liu, Rudi Beyaert, Mayland Chang, Qi Li, Yihai Cao
Abstract
Tumor neoantigens arising from somatic mutations in the cancer genome are less likely to be subject to central immune tolerance and are therefore attractive targets for vaccine immunotherapy. We utilized whole-exome sequencing, RNA sequencing (RNASeq), and an in silico immunogenicity prediction algorithm, NetMHC, to generate a neoantigen-targeted vaccine, PancVAX, which was administered together with the STING adjuvant ADU-V16 to mice bearing pancreatic adenocarcinoma (Panc02) cells. PancVAX activated a neoepitope-specific T cell repertoire within the tumor and caused transient tumor regression. When given in combination with two checkpoint modulators, namely anti–PD-1 and agonist OX40 antibodies, PancVAX resulted in enhanced and more durable tumor regression and a survival benefit. The addition of OX40 to vaccine reduced the coexpression of T cell exhaustion markers, Lag3 and PD-1, and resulted in rejection of tumors upon contralateral rechallenge, suggesting the induction of T cell memory. Together, these data provide the framework for testing personalized neoantigen-based combinatorial vaccine strategies in patients with pancreatic and other nonimmunogenic cancers.
Authors
Heather L. Kinkead, Alexander Hopkins, Eric Lutz, Annie A. Wu, Mark Yarchoan, Kayla Cruz, Skylar Woolman, Teena Vithayathil, Laura H. Glickman, Chudi O. Ndubaku, Sarah M. McWhirter, Thomas W. Dubensky Jr., Todd D. Armstrong, Elizabeth M. Jaffee, Neeha Zaidi
Abstract
Chimeric antigen receptors (CARs) have an antigen-binding domain fused to transmembrane, costimulatory, and CD3ζ domains. Two CARs with regulatory approval include a CD28 or 4-1BB costimulatory domain. While both CARs achieve similar clinical outcomes, biologic differences have become apparent but not completely understood. Therefore, in this study we aimed to identify mechanistic differences between 4-1BB and CD28 costimulation that contribute to the biologic differences between the 2 CARs and could be exploited to enhance CAR T cell function. Using CD19-targeted CAR T cells with 4-1BB we determined that enhancement of T cell function is driven by NF-κB. Comparison to CAR T cells with CD28 also revealed that 4-1BB is associated with more antiapoptotic proteins and dependence on persistence for B cell killing. While TNF receptor–associated factor 2 (TRAF2) has been presupposed to be required for 4-1BB costimulation in CAR T cells, we determined that TRAF1 and TRAF3 are also critical. We observed that TRAFs impacted CAR T viability and proliferation, as well as cytotoxicity and/or cytokines, in part by regulating NF-κB. Our study demonstrates how 4-1BB costimulation in CAR T cells impacts antitumor eradication and clinical outcomes and has implications for enhanced CAR design.
Authors
Gongbo Li, Justin C. Boucher, Hiroshi Kotani, Kyungho Park, Yongliang Zhang, Bishwas Shrestha, Xuefeng Wang, Lawrence Guan, Nolan Beatty, Daniel Abate-Daga, Marco L. Davila
Abstract
Sarcomas are still unsolved therapeutic challenges. Cancer stem cells are believed to contribute to sarcoma development, but lack of specific markers prevents their characterization and targeting. Here, we show that calpain-6 expression is associated with cancer stem cell features. In mouse models of bone sarcoma, calpain-6–expressing cells have unique tumor-initiating and metastatic capacities. Calpain-6 levels are especially high in tumors that have been successfully propagated in mouse to establish patient-derived xenografts. We found that calpain-6 levels are increased by hypoxia in vitro and calpain-6 is detected within hypoxic areas in tumors. Furthermore, calpain-6 expression depends on the stem cell transcription network that involves Oct4, Nanog, and Sox2 and is activated by hypoxia. Calpain-6 knockdown blocks tumor development in mouse and induces depletion of the cancer stem cell population. Data from transcriptomic analyses reveal that calpain-6 expression in sarcomas inversely correlates with senescence markers. Calpain-6 knockdown suppresses hypoxia-dependent prevention of senescence entry and also promotion of autophagic flux. Together, our results demonstrate that calpain-6 identifies sarcoma cells with stem-like properties and is a mediator of hypoxia to prevent senescence, promote autophagy, and maintain the tumor-initiating cell population. These findings open what we believe is a novel therapeutic avenue for targeting sarcoma stem cells.
Authors
Caroline Andrique, Laetitia Morardet, Laetitia K. Linares, Madi Y. Cissé, Candice Merle, Frédéric Chibon, Sylvain Provot, Eric Haÿ, Hang-Korng Ea, Martine Cohen-Solal, Dominique Modrowski
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