Platinum-based chemotherapy in combination with immune-checkpoint inhibitors is the current standard of care for patients with advanced lung adenocarcinoma (LUAD). However, tumor progression evolves in most cases. Therefore, predictive biomarkers are needed for better patient stratification and for the identification of new therapeutic strategies, including enhancing the efficacy of chemotoxic agents. Here, we hypothesized that discoidin domain receptor 1 (DDR1) may be both a predictive factor for chemoresistance in patients with LUAD and a potential target positively selected in resistant cells. By using biopsies from patients with LUAD, KRAS-mutant LUAD cell lines, and in vivo genetically engineered KRAS-driven mouse models, we evaluated the role of DDR1 in the context of chemotherapy treatment. We found that DDR1 is upregulated during chemotherapy both in vitro and in vivo. Moreover, analysis of a cohort of patients with LUAD suggested that high DDR1 levels in pretreatment biopsies correlated with poor response to chemotherapy. Additionally, we showed that combining DDR1 inhibition with chemotherapy prompted a synergistic therapeutic effect and enhanced cell death of KRAS-mutant tumors in vivo. Collectively, this study suggests a potential role for DDR1 as both a predictive and prognostic biomarker, potentially improving the chemotherapy response of patients with LUAD.
Marie-Julie Nokin, Elodie Darbo, Camille Travert, Benjamin Drogat, Aurélie Lacouture, Sonia San José, Nuria Cabrera, Béatrice Turcq, Valérie Prouzet-Mauleon, Mattia Falcone, Alberto Villanueva, Haiyun Wang, Michael Herfs, Miguel Mosteiro, Pasi A. Jänne, Jean-Louis Pujol, Antonio Maraver, Mariano Barbacid, Ernest Nadal, David Santamaría, Chiara Ambrogio
Purpose: There is a rapidly evolving portfolio of immune therapeutic modulators, but the relative incidence of immune targets in human gliomas is unknown. In order to prioritize available immune therapeutics, immune profiling across glioma grades was conducted followed by preclinical determinations of therapeutic effect in immune competent mice harboring gliomas. Methods: CD4+ and CD8+ T cells and CD11b+ myeloid cells were isolated from the blood of healthy donors and the blood and tumors of newly diagnosed and recurrent glioma patients and profiled for the expression of immune modulatory targets with an available therapeutic. Preclinical murine models of glioma were used to assess therapeutic efficacy of agents targeting the most frequently expressed immune targets. Immune effector function was analyzed in the setting of glioma induced immune suppression. Results: In glioma patients, the adenosine-CD73-CD39 immune suppressive pathway was most frequently expressed, followed by PD-1. CD73 expression was upregulated on immune cells by 2-hydroxygluterate in IDH1 mutant glioma patients. In multiple murine glioma models, including those that express CD73, adenosine receptor inhibitors demonstrated a modest therapeutic response; however, the addition of other inhibitors of the adenosine pathway did not further enhance this therapeutic effect. Although adenosine receptor inhibitors could recover immunological effector functions in T cells after the engagement of this pathway, immune recovery was impaired in the presence of gliomas, indicating that irreversible immune exhaustion limits the effectiveness of inhibitors of the adenosine pathway in glioma patients. Conclusions: This study illustrates vetting steps that should be considered prior to clinical trial implementation for immunotherapy resistant cancers including testing an agents ability to restore immunological function in the context of intended use.
Martina Ott, Karl-Heinz Tomaszowski, Anantha Marisetty, Ling-Yuan Kong, Jun Wei, Maya Duna, Katia Blumberg, Xiaorong Ji, Carmen B Jacobs, Gregory N. Fuller, Lauren A. Langford, Jason T. Huse, James P. Long, Jian Hu, Shulin Li, Jeffrey S. Weinberg, Sujit Prabhu, Raymond Sawaya, Sherise D. Ferguson, Ganesh Rao, Frederick F. Lang, Michael A. Curran, Amy B. Heimberger
Aromatase inhibitors (AIs) reduce breast cancer recurrence and prolong survival, but up to 30% of patients exhibit recurrence. Using a genome-wide association study of patients entered on MA.27, a phase III randomized trial of anastrozole vs exemestane, we identified a SNP in CUB And Sushi Multiple Domains 1 (CSMD1) associated with breast cancer free interval, with the variant allele associated with fewer distant recurrences. Mechanistically, CSMD1 regulates CYP19 expression in a SNP-, and drug-dependent fashion and this regulation is different among three AIs, anastrozole, exemestane, and letrozole. Overexpression of CSMD1 sensitized AI-resistant cells to anastrozole but not to the other two AIs. The SNP in CSMD1 that was associated with increased CSMD1 and CYP19 expression levels increased anastrozole sensitivity, but not letrozole or exemestane sensitivity. Anastrozole degrades estrogen receptor α (ERα), especially in the presence of estradiol (E2). ER positive breast cancer organoids and AI- or fulvestrant-resistant breast cancer cells were more sensitive to anastrozole plus E2 than to AI alone. Our findings suggest that the CSMD1 SNP might help to predict AI response and anastrozole plus E2 serves as a potential new therapeutic strategy for patients with AI- or fulvestrant-resistant breast cancers.
Junmei Cairns, James N. Ingle, Tanda T. M. Dudenkov, Krishna R. Kalari, Erin E. Carlson, Jie Na, Aman U. Buzdar, Mark E. Robson, Matthew J. Ellis, Paul E. Goss, Lois E. Shepherd, Barbara Goodnature, Matthew P. Goetz, Richard M. Weinshilboum, Hu Li, Mehrab Ghanat Bari, Liewei Wang
Cancer is instigated by mutator phenotypes, including deficient mismatch repair and p53-associated chromosomal instability. More recently, a distinct class of cancers was identified with unusually high mutational loads due to heterozygous amino acid substitutions (most commonly P286R) in the proofreading domain of DNA polymerase ε, the leading strand replicase encoded by POLE. Immunotherapy has revolutionized cancer treatment, but new model systems are needed to recapitulate high mutational burdens characterizing human cancers and permit study of mechanisms underlying clinical responses. Here, we show that activation of a conditional LSL-PoleP286R allele in endometrium is sufficient to elicit in all animals endometrial cancers closely resembling their human counterparts, including very high mutational burden. Diverse investigations uncovered potentially novel aspects of Pole-driven tumorigenesis, including secondary p53 mutations associated with tetraploidy, and cooperation with defective mismatch repair through inactivation of Msh2. Most significantly, there were robust antitumor immune responses with increased T cell infiltrates, accelerated tumor growth following T cell depletion, and unfailing clinical regression following immune checkpoint therapy. This model predicts that human POLE-driven cancers will prove consistently responsive to immune checkpoint blockade. Furthermore, this is a robust and efficient approach to recapitulate in mice the high mutational burdens and immune responses characterizing human cancers.
Hao-Dong Li, Changzheng Lu, He Zhang, Qing Hu, Junqiu Zhang, Ileana C. Cuevas, Subhransu S. Sahoo, Mitzi Aguilar, Elizabeth G. Maurais, Shanrong Zhang, Xiaojing Wang, Esra A. Akbay, Guo-Min Li, Bo Li, Prasad Koduru, Peter Ly, Yang-Xin Fu, Diego H. Castrillon
Pancreatic ductal adenocarcinoma (PDAC) is characterized by a relative paucity of cancer cells that are surrounded by an abundance of non-tumor cells and extracellular matrix, known as stroma. The interaction between stroma and cancer cells contributes to poor outcome, but how proteins from these individual compartments drive aggressive tumor behavior is not known. Here, we report the proteomic analysis of laser-capture microdissected (LCM) PDAC samples. We isolated stroma, tumor, and bulk samples from a cohort with long- and short-term survivors. Compartment-specific proteins were measured by mass spectrometry, yielding the largest PDAC proteome landscape to date. These analyses revealed that in bulk analysis, tumor-derived proteins were typically masked and that LCM was required to reveal biology and novel prognostic markers. We validated tumor CALB2 and stromal COL11A1 expression as compartment-specific prognostic markers. We identified and functionally addressed the contributions of the tumor cell receptor EPHA2 to tumor cell viability and motility, underscoring the value of compartment-specific protein analysis in PDAC.
Tessa Y.S. Le Large, G. Mantini, Laura L. Meijer, T.V. Pham, N. Funel, Nicole C.T. van Grieken, B. Kok, Jaco C. Knol, H.W.M. van Laarhoven, S.R. Piersma, C.R. Jimenez, G. Kazemier, E. Giovannetti, M.F. Bijlsma
Triple-negative breast cancers (TNBCs) are highly heterogeneous and aggressive, with high mortality rates. Although TNBC is typically more responsive to chemotherapy than other breast cancer subtypes, many patients develop chemo-resistance. The molecular processes contributing to chemo-resistance, and the roles of tumor cell-stromal crosstalk in establishing chemo-resistance are complex and largely unclear. Here we report molecular studies of paired TNBC patient-derived xenografts (PDX) established from patient biopsies before and after the development of chemo-resistance. Interestingly, the chemo-resistant model acquired a distinct KRASQ61R mutation that activates K-Ras. The chemo-resistant KRAS-mutant model showed gene expression and proteomic changes indicative of altered tumor cell metabolism. Specifically, KRAS-mutant PDXs exhibit increased redox ratios and decreased activation of AMPK, a protein involved in responding to metabolic homeostasis. Additionally, the chemo-resistant model exhibited increased immunosuppression including expression of CXCL1 and CXCL2, cytokines responsible for recruiting immunosuppressive leukocytes to tumors. Notably, chemo-resistant KRAS-mutant tumors harbored increased numbers of granulocytic myeloid-derived suppressor cells (gMDSCs). Interestingly, previously established gene expression signatures of Ras/MAPK activity correlated with myeloid/neutrophil-recruiting CXCL1/2 expression and negatively with T-cell recruiting chemokines (CXCL9/10/11) across TNBC patients, even in the absence of KRAS mutations. Importantly, MEK inhibition induced tumor suppression in mice while simultaneously reversing metabolic and immunosuppressive phenotypes including chemokine production and gMDSC tumor recruitment in the chemo-resistant KRAS mutant tumors. These results suggest that Ras/MAPK pathway inhibitors may be effective in some breast cancer patients to reverse Ras/MAPK-driven tumor metabolism and immunosuppression, particularly in the setting of chemo-resistance.
Derek A. Franklin, Joe T. Sharick, Paula I. Gonzalez-Ericsson, Violeta Sanchez, Phillip Dean, Susan R. Opalenik, Stefano Cairo, Jean-Gabriel Judde, Michael T. Lewis, Jenny C. Chang, Melinda E. Sanders, Rebecca S. Cook, Melissa C. Skala, Jennifer Bordeaux, Jehovana Orozco Bender, Christine A. Vaupel, Gary Geiss, Douglas Hinerfeld, Justin M. Balko
One of the major challenges in using pancreatic cancer patient-derived organoids (PDOs) in precision oncology is the time from biopsy to functional characterization. This is particularly true for biopsy specimen with limited tumor cell yield, typical characteristics of biopsies from endoscopic ultrasound-guided fine needle aspirations (EUS-FNAs).Here, we tested conditioned media of individual PDOs for cell-free tumor DNA (cfDNA) to detect driver mutations already early on during the expansion process in order to accelerate the genetic characterization of PDOs as well as subsequent functional testing. Importantly, genetic alterations detected in the PDO supernatant, collected as early as 72h after biopsy, recapitulate the mutational profile of the primary tumor indicating suitability of this approach to subject PDOs to drug testing in a reduced timeframe. In addition, we demonstrate that this workflow is practicable even in patients of whom the amount of tumor material was not sufficient for molecular characterization by established means.Our findings demonstrate that generating PDOs from very limited biopsy material permits molecular profiling and drug testing. With our approach this can be achieved in a rapid and feasible fashion with broad implications in clinical practice.
Zahra Dantes, Hsi-Yu Yen, Nicole Pfarr, Christof Winter, Katja Steiger, Alexander Muckenhuber, Alexander Hennig, Sebastian Lange, Thomas Engleitner, Rupert Öllinger, Roman Maresch, Felix Orben, Irina Heid, Georgios A. Kaissis, Kuangyu Shi, Geoffrey J. Topping, Fabian Stögbauer, Matthias Wirth, Katja Peschke, Aristeidis Papargyriou, Massoud Rezaee-Oghazi, Karin Feldmann, Arlett P. G. Schäfer, Raphela Ranjan, Clara Lubeseder-Martellato, Daniel E. Stange, Thilo Welsch, Marc E. Martignoni, Güralp Onur Ceyhan, Helmut Friess, Alexander Herner, Lucia Liotta, Matthias Treiber, Guido von Figura, Mohamed Abdelhafez, Peter Klare, Christoph Schlag, Hana Algül, Jens T. Siveke, Rickmer F. Braren, Gregor Weirich, Wilko Weichert, Dieter Saur, Roland Rad, Roland Schmid, Günter Schneider, Maximilian Reichert
Dendritic cells (DCs) are critical component of immune responses in cancer primarily due to their ability to cross-present tumor associated antigens. Cross-presentation by DCs in cancer is impaired, which may represent one of the obstacles for the success of cancer immunotherapies. Here, we report that polymorphonuclear myeloid derived suppressor cells (PMN-MDSC) blocked cross-presentation by DCs without affecting direct presentation of antigens by these cells. This effect did not require direct cell-cell contact and was associated with transfer of lipids. Neutrophils (PMN) and PMN-MDSC transferred lipid to DCs equally well, however PMN did not affect DC cross-presentation. PMN-MDSC generate oxidatively truncated lipids previously shown to be involved in impaired cross-presentation by DCs. Accumulation of oxidized lipids in PMN-MDSC was dependent on myeloperoxidase (MPO). MPO deficient PMN-MDSC did not affect cross-presentation by DCs. Cross-presentation of tumor associated antigens in vivo by DCs was improved in MDSC depleted or tumor-bearing MPO KO mice. Pharmacological inhibition of MPO in combination with checkpoint blockade reduced tumor progression in different tumor models. These data suggest MPO-driven lipid peroxidation in PMN-MDSC as a possible non-cell autonomous mechanism of inhibition of antigen cross-presentation by DCs and propose MPO as potential therapeutic target to enhance the efficacy of current immunotherapies for cancer patients.
Alessio Ugolini, Vladimir Tyurin, Yulia Tyurina, Evgenii Tsyganov, Laxminarasimha Donthireddy, Valerian E Kagan, Dmitry I. Gabrilovich, Filippo Veglia
Expression of immune checkpoint ligands (ICLs) is necessary to trigger the inhibitory signal via immune checkpoint receptors (ICRs) in exhausted T cells under tumor immune microenvironment. Nevertheless, ICL expression profile in cancer patients has not been investigated. Using previously reported RNA-seq datasets, we found that expression of ICLs was patient-specific but their co-expression can be patterned in non-small-cell lung cancers (NSCLCs). Since the expressions of PD-L1 and PVR among various ICLs were independently regulated, we could stratify the patients, who were treated with anti-PD-1 later, into four groups according to the expression level of PD-L1 and PVR. Of interest, high PVR and low PVR expressions in PD-L1-expressing patients enriched non-responders and responders to PD-1 blockade, respectively, helping in further selection of responders. Using genetically engineered cancer model, we also found that PVR-deficient and PD-L1-sufficient tumor-bearing mice were highly sensitive to anti-PD-1 therapy, whereas PVR-sufficient and PD-L1-deficient tumor-bearing mice were resistant to anti-PD-1 therapy. Taken together, our study provides a concept that combinatorial expression patterns of PVR and PD-L1 are a key determinant for PD-1 blockade and furthermore suggest a better therapeutic usage of immune checkpoint blockades (ICBs).
Bo Ryeong Lee, Sehyun Chae, Jihyun Moon, Myeong Joon Kim, Hankyu Lee, Hyuk Wan Ko, Byoung Chul Cho, Hyo Sup Shim, Daehee Hwang, Hye Ryun Kim, Sang-Jun Ha
Oxidative stress and inadequate redox homeostasis is crucial for tumor initiation and progression. MTH1 (NUDT1) enzyme prevents incorporation of oxidized dNTPs by sanitizing the deoxynucleoside triphosphate (dNTP) pool and is therefore vital for the survival of tumor cells. MTH1 inhibition has been found to inhibit the growth of several experimental tumors, but its role in mesothelioma progression remained elusive. Moreover, although MTH1 is nonessential to normal cells, its role in survival of host cells in tumor milieu, especially tumor endothelium, is unclear. We validated a clinically relevant MTH1 inhibitor (Karonudib) in mesothelioma treatment using human xenografts and syngeneic murine models. We show that MTH1 inhibition impedes mesothelioma progression and that inherent tumoral MTH1 levels are associated with a tumor’s response. We also identified tumor endothelial cells as selective targets of Karonudib and propose a model of intercellular signaling among tumor cells and bystander tumor endothelium. We finally determined the major biological processes associated with elevated MTH1 gene expression in human mesotheliomas.
Sophia F. Magkouta, Apostolos G. Pappas, Photene C. Vaitsi, Panagiotis C. Agioutantis, Ioannis S. Pateras, Charalampos A. Moschos, Marianthi P. Iliopoulou, Chrysavgi N. Kosti, Heleni V. Loutrari, Vassilis G. Gorgoulis, Ioannis T. Kalomenidis
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