Oncology
Abstract
We conceived of a type of antitumor mechanism of action by which a soluble target in the tumor microenvironment, such as a tumor-driving growth factor, can be phagocytized along with cancer cells via antibody-dependent cellular phagocytosis (ADCP) using an antibody bispecific for the soluble target and a solid target overexpressed on the cancer cell surface. We explored this concept through engineering bispecific antibodies (BsAbs) co-targeting human epidermal growth factor receptor-2 (HER2) and vascular endothelial growth factor A (VEGFA) in an scFv-IgG format (VHS). We showed that the HER2-VEGFA BsAbs but not the parental antibodies alone or in combination induced co-phagocytosis of VEGFA and HER2-overexpressing cancer cells by tumor-associated macrophages via ADCP. In both immunocompromised and immunocompetent mice with aggressive tumors, the BsAbs demonstrated greater anti-metastasis activity and produced a greater survival benefit than the parental antibodies alone or in combination, in a manner dependent on Fcγ receptors on the macrophages. Our results provide proof of the concept that HER2-VEGFA BsAbs achieve enhanced antitumor activity by leveraging HER2 overexpressed on the cancer cell surface to induce co-phagocytosis of VEGFA. Our findings warrant clinical testing of the strategy to treat metastasis and recurrence of HER2-overexpressing solid tumors that respond to anti-VEGFA therapy.
Authors
Yang Lu, Songbo Qiu, Zhen Fan
Abstract
BACKGROUND. Emerging evidence indicates a reduced incidence of multiple cancers in users of Glucagon-like peptide-1 receptor agonists (GLP-1RAs), drugs widely used for glycemic control and weight reduction that modulate several key regulators of metabolism. We sought to examine their association with non-small cell lung cancer (NSCLC) outcomes in overweight and obese patients and gain mechanistic insights from mouse models. METHODS. Two clinical cohorts of overweight and obese NSCLC patients—one undergoing surgical resection (n=1,177, 71 GLP-1RA users) and another receiving immune checkpoint inhibitors (ICIs; n=300, 10 GLP-1RA users), were propensity score matched for relevant covariates and analyzed for clinical outcomes. RESULTS. GLP-1RA use was associated with increased recurrence-free survival in overweight and obese patients (HR=0.41 [95%CI=0.16-1.04], p=0.026) after lobectomy. GLP-1RA treatment reduced tumor burden in obese but not normal-weight mice and altered the frequency and phenotypes of leukocyte populations and gene expression patterns in obese tumors, crucial to cancer progression and anti-tumor immunity. Concurrent GLP-1RA and immunotherapy was associated with improved overall (0.41 [0.16-1.01], 0.027) and progression-free survival (HR=0.31, [0.10-0.94], 0.019) for patients with advanced NSCLC. CONCLUSIONS. In our cohort, GLP-1RAs enhanced lung cancer-specific clinical outcomes and augment immunotherapy efficacy. Preclinical evidence suggested this effect to be obesity-restricted and mediated by immune modulation of the tumor microenvironment. FUNDING. This work was supported by a generous donation from Mr. George Duke to SY; W81XWH-21-1-0377, (GM147497), and RSG-22-071-01-TBE to VRS; 1R01 CA255515-01A1 to SY and JB; and NIH/NCI Cancer Center Support Grants P30CA013696 and P30CA016056.
Authors
Akhil Goud Pachimatla, Bailey Fitzgerald, Joyce Ogidigo, Meera Bhatia, Randall J. Smith Jr., Kalyan Ratnakaram, Sukumar Kalvapudi, Yeshwanth Vedire, Deschana Washington, Robert Vethanayagam rr, Hua-Hsin Hsiao, Spencer Rosario, Viraj R. Sanghvi, Joseph Barbi, Sai Yendamuri
Abstract
We assessed the therapeutic efficacy of a semiallogeneic dendritic cell (DC) vaccine in comparison to a syngeneic one for suppression of B16-F10 and TC-1 tumors. Syngeneic bone marrow–derived DCs (BMDCs) were generated from C57BL/6J mice and semiallogeneic BMDCs with a mutation in either MHC class I or II were generated from B6.C-H2-Kbm1/ByJ or B6(C)-H2-Ab1bm12/KhEgJ mice, respectively. We demonstrated in vivo and in vitro that the MHC class II semiallogeneic BMDC vaccine had superior efficacy over the syngeneic and the MHC class I semiallogeneic BMDC vaccine, providing allogeneic CD4+ T cell help to enhance the antitumor CD8+ T cell response through allogeneic stimulation by the mutant MHC class II molecules. We discovered that this help was induced only at an early stage of tumor growth and at a later stage of tumor growth; combining our BMDC vaccine with Treg depletion enhanced tumor suppression. We demonstrated the improved efficacy of a semiallogeneic BMDC vaccine that kept tumor-peptide presentation intact on syngeneic MHC class I molecules so that mutant MHC class II could provide allogeneic help. This strategy should enable promising new DC-based cancer immunotherapies, offering an alternative to autologous DC vaccines by incorporating allogenicity as an adjuvant.
Authors
Noriko Seishima, William Becker, Purevdorj B. Olkhanud, Hoyoung M. Maeng, Miguel A. Lopez-Lago, William V. Williams, Jay A. Berzofsky
Abstract
While the accumulation of tumor-associated macrophages (TAMs) in glioblastoma (GBM) has been well documented, targeting TAMs has thus far yielded limited clinical success in slowing GBM progression due, in part, to an incomplete understanding of TAM function. Using an engineered 3D hydrogel–based model of the brain tumor microenvironment (TME), we show that M2-polarized macrophages stimulate transcriptional and phenotypic changes in GBM stem cells (GSCs) closely associated with the highly aggressive and invasive mesenchymal subtype. By combining proteomics with GBM patient single-cell transcriptomics, we identify multiple TAM-secreted proteins with putative proinvasive functions and validate TGF-β induced (TGFBI, also known as BIGH3) as a targetable TAM-secreted tumorigenic factor. Our work highlights the utility of coupling multiomics analyses with engineered TME models to investigate TAM–cancer cell crosstalk and offers insights into TAM function to guide TAM-targeting therapies.
Authors
Erin A. Akins, Dana Wilkins, Zaki Abou-Mrad, Kelsey Hopland, Robert C. Osorio, Kenny K.H. Yu, Manish K. Aghi, Sanjay Kumar
Abstract
Cancer-associated fibroblasts (CAFs) are part of the tumor microenvironment (TME) that enable cancer cells to establish metastases, but the mechanisms of these interactions are not fully known. Herein, we identified a paracrine mechanism in which CAF-secreted asporin (ASPN) activated ErbB signaling and subsequent migration of adjacent prostate cancer cells. Our data support that ASPN bound directly to the ligand binding domain of human epidermal growth factor 3 (HER3) and induced HER2/HER3 heterodimerization and activation of the PI3K, MAPK, and calcium pathways. Genetic and therapeutic inhibition of HER2/HER3 ablated ASPN-induced signaling and migration. Clinically, ASPN was detected in the stroma of HER2/HER3-expressing human metastatic prostate cancer, supporting the clinical relevance of these findings and highlighting a potential therapeutic vulnerability. Antibody-drug conjugate (ADC) therapies designed to target HER2 (trastuzumab-deruxtecan) or HER3 (patritumab-deruxtecan) significantly diminished prostate cancer cell growth in vitro and tumor size in vivo, despite Aspn in the TME. Collectively, these findings indicate ASPN functions as a HER3 ligand to induce cellular migration, and inhibition with anti-HER2 or anti-HER3 ADC therapies highlights potential clinical utility for patients with metastatic castration-resistant prostate cancer that expresses HER2 or HER3.
Authors
Amanda B. Hesterberg, Hong Yuen Wong, Jorgen Jackson, Monika Antunovic, Brenda L. Rios, Evan Watkins, Riley E. Bergman, Brad A. Davidson, Sarah E. Ginther, Diana Graves, Elliott F. Nahmias, Jared A. Googel, Lillian B. Martin, Violeta Sanchez, Paula I. Gonzalez-Ericsson, Quanhu Sheng, Benjamin P. Brown, Jens Meiler, Kerry R. Schaffer, Jennifer B. Gordetsky, Ben H. Park, Paula J. Hurley
Abstract
Radiotherapy triggers chemokine release and leukocyte infiltration in pre-clinical models through activation of the senescence-associated secretory phenotype (SASP). However, effects of irradiation on senescence and SASP in human tissue and in the context of particle radiotherapy remain unclear. Here, we analyzed chemokine patterns after radiotherapy of human pancreatic tumors and cancer cell lines. We show that irradiated tumor cells co-express SASP chemokines in defined modules. These chemokine modules correlated with infiltration of distinct leukocyte subtypes expressing cognate receptors. We developed a patient-derived pancreatic tumor explant system, which confirmed our identified radiation-induced chemokine modules. Chemokine modules were partially conserved in cancer cells in response to photon and particle irradiation showing a dose-dependent plateau effect and induced subsequent migration of NK and T cell populations. Hence, our work reveals redundant interactions of cancer cells and immune cells in human tissue, suggesting that targeting multiple chemokines is required to efficiently perturb leukocyte infiltration after photon or particle radiotherapy.
Authors
Joscha A. Kraske, Michael M. Allers, Aleksei Smirnov, Bénédicte Lenoir, Azaz Ahmed, Meggy Suarez-Carmona, Mareike Hampel, Damir Krunic, Alexandra Tietz-Dalfuß, Tizian Beikert, Jonathan M. Schneeweiss, Stephan Brons, Dorothee Albrecht, Thuy Trinh, Muzi Liu, Nathalia A. Giese, Christin Glowa, Jakob Liermann, Ramon Lopez Perez, Dirk Jäger, Jürgen Debus, Niels Halama, Peter E. Huber, Thomas Walle
Abstract
The tumor microenvironment (TME) significantly impacts cancer progression, yet traditional animal models do not fully recapitulate the situation in humans. To address this, we developed tumor-derived precision lung slices (TD-PCLS), an ex vivo platform for studying the lung TME and evaluating therapies. TD-PCLS, viable for 8 to 10 days, preserve the heterogeneity and metabolic activity of primary tumors, as confirmed by seahorse analysis. Using multispectral FACS and phenocycler multiplex imaging, we spatially profiled TME components and cancer cell functionality. Additionally, TD-PCLS revealed patient-specific responses to chemo- and immunotherapies. To complement TD-PCLS, we established tumor-cell-seeded PCLS (TCS-PCLS) by introducing tumor and immune cells into healthy lung slices. This model highlighted macrophage-tumor interactions as critical for tumor cell proliferation, migration, and immune modulation. Together, these platforms provide a robust tool for lung cancer research, enabling precision medicine and advancing therapeutic discovery.
Authors
Siavash Mansouri, Annika Karger, Clemens Ruppert, Marc A. Schneider, Andreas Weigert, Rajender Nandigama, Blerina Aliraj, Lisa Strotmann, Anoop V. Cherian, Diethard Pruefer, Peter Dorfmuller, Ludger Fink, Ibrahim Alkoudmani, Stefan Gattenlöhner, Bastian Eul, Andre Althoff, Peter Kleine, Hauke Winter, Andreas Guenther, Ardeschir Ghofrani, Soni S. Pullamsetti, Friedrich Grimminger, Werner Seeger, Rajkumar Savai
Abstract
More than one third of patients with glioblastoma experience tumour progression during adjuvant therapy. In this study, we performed a high-throughput drug repurposing screen of FDA-approved agents capable of crossing the blood-brain barrier that to find agents to counteract acquired or inherent glioma cell resistance to temozolomide-associated cytotoxicity. We identified the cholesterol processing inhibitor, lomitapide, as a potential chemosensitizer in glioblastoma. In vitro treatment of temozolomide-resistant glioblastoma cells with lomitapide resulted in decreased intracellular ubiquinone levels and sensitized cells to temozolomide-induced ferroptosis. Concomitant treatment with lomitapide and temozolomide (TMZ) prolonged survival and delayed tumour recurrence in a mouse glioblastoma model, compared to treatment with TMZ alone. Our data identified lomitapide as a potential adjunct for treatment of temozolomide-resistant glioblastoma.
Authors
Alyona Ivanova, Taylor M. Wilson, Kimia Ghannad-Zadeh, Esmond Tse, Robert Flick, Megan Wu, Sunit Das
Abstract
Malignancies increase the risk for thrombosis and metastasis dependent on complex interactions of innate immune cells, platelets, and the coagulation system. Immunosuppressive functions of platelets and macrophage-derived coagulation factors in the tumor microenvironment (TME) drive tumor growth. Here we show that patients with malignancies and tumor-bearing mice have increased levels of coagulation factor (F) X expressing circulating monocytes engaged in platelet aggregate formation. This interaction and resulting thrombin generation on platelets interferes with monocyte differentiation and antigen uptake of antigen-presenting cells (APCs). Myeloid cell-specific deletion of FX or abrogated FXa signaling via protease activated receptor 2 (PAR2) averts the suppressive activity of platelets on tumor cell debris uptake and promotes the immune stimulatory activity of APCs in the TME. Myeloid cell FXa-PAR2 signaling deficiency specifically enhances activation of the cGAS-STING-IFN-I pathway with a resulting expansion of antigen experienced progenitor exhausted CD8+ T cells. Pharmacological blockade of FXa with direct oral anticoagulants expands T cell priming-competent immune cells in the TME and synergizes with the reactivation of exhausted CD8+ T cells by immune checkpoint inhibitors for improved anti-tumor responses. These data provide mechanistic insights into the emerging clinical evidence demonstrating the translational potential of FXa inhibition to synergize with immunotherapy.
Authors
Petra Wilgenbus, Jennifer Pott, Sven Pagel, Claudius Witzler, Jennifer Royce, Federico Marini, Sabine Reyda, Thati Madhusudhan, Thomas Kindler, Anne Hausen, Matthias M. Gaida, Hartmut Weiler, Wolfram Ruf, Claudine Graf
Abstract
RNA splicing factor SF3B1 is one of the most recurrently mutated genes in chronic lymphocytic leukemia (CLL) and frequently co-occurs with chromosome 13q deletion (del(13q)). This combination is associated with poor prognosis in CLL, suggesting these lesions increase CLL aggressiveness. While del(13q) in murine B cells (Mdr mice), but not expression of Sf3b1-K700E, drives the initiation of CLL, we hypothesize that SF3B1 mutation accelerates CLL progression. In this study, we crossed mice with a B-cell-specific Sf3b1-K700E allele with Mdr mice to determine the impact of Sf3b1 mutation on CLL progression. We found that the co-occurrence of these two lesions in murine B cells caused acceleration of CLL. We showed that Sf3b1-K700E impacted alternative RNA splicing of Nfatc1 and activated mTOR signaling and the MYC pathway, contributing to CLL acceleration. Moreover, concurrent inhibition of RNA splicing and mTOR pathways led to cell death in vitro and in vivo in murine CLL cells with SF3B1 mutation and del(13q). Our results thus suggest that SF3B1 mutation contributes to the aggressiveness of CLL by activating the mTOR pathway through alternative splicing of Nfatc1, providing a rationale for targeting mTOR and RNA splicing in the subset of CLL patients with both SF3B1 mutations and del(13q).
Authors
Bo Zhang, Prajish Iyer, Meiling Jin, Elisa ten Hacken, Zachary Cartun, Kevyn L. Hart, Mike Fernandez, Kristen Stevenson, Laura Rassenti, Emanuela M. Ghia, Thomas J. Kipps, Donna Neuberg, Ruben Carrasco, Wing Chan, Joo Y. Song, Yu Hu, Catherine Wu, Lili Wang
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