21 results on '"Samarth Hegde"'
Search Results
2. 650 Neoadjuvant ezabenlimab or pembrolizumab in combination with an anti-SIRPα antibody in resectable colorectal cancer
- Author
-
Noam Harpaz, Samarth Hegde, Lisa Fitzgerald, Stephen Ward, Miriam Merad, Thomas Marron, Zheng Zhu, Qingqing Liu, Celina Ang, Deborah Doroshow, Umut Sarpel, Kathy Wu, Ana Acuna-Villaorduna, Natalie Lucas, Nicholas Venturini, Raphaël Mattiuz, Clotilde Hennequin, Jessica Le Berichel, Theodore Chin, Amanda Reid, Leanna Troncoso, David Greenwald, Ari Grinspan, Steve Itzkowitz, Aimee L Lucas, Dana Zalkin, Peter Kozuch, Sergey Khaitov, Alex Ky-Miyasaka, Randolph Steinhagen, Patricia Sylla, Gunther Kretschmar, John Paulsen, Xintong Wang, Alexandros D Polydorides, Deirdre Cohen, Gabriela Fazilov, Gary Shelton, Amber Cameron, and Megan Yuan
- Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Published
- 2023
- Full Text
- View/download PDF
3. Sterile Inflammation Enhances ECM Degradation in Integrin β1 KO Embryonic Skin
- Author
-
Ambika S. Kurbet, Samarth Hegde, Oindrila Bhattacharjee, Srujan Marepally, Praveen K. Vemula, and Srikala Raghavan
- Subjects
Biology (General) ,QH301-705.5 - Abstract
Epidermal knockout of integrin β1 results in complete disorganization of the basement membrane (BM), resulting in neonatal lethality. Here, we report that this disorganization is exacerbated by an early embryonic inflammatory response involving the recruitment of tissue-resident and monocyte-derived macrophages to the dermal-epidermal junction, associated with increased matrix metalloproteinase activity. Remarkably, the skin barrier in the integrin β1 knockout animals is intact, suggesting that this inflammatory response is initiated in a sterile environment. We demonstrate that the molecular mechanism involves de novo expression of integrin αvβ6 in the basal epidermal cells, which activates a TGF-β1 driven inflammatory cascade resulting in upregulation of dermal NF-κB in a Tenascin C-dependent manner. Importantly, treatment of β1 KO embryos in utero with small molecule inhibitors of TGF-βR1 and NF-κB results in marked rescue of the BM defects and amelioration of immune response, revealing an unconventional immuno-protective role for integrin β1 during BM remodeling.
- Published
- 2016
- Full Text
- View/download PDF
4. TREM2 macrophages drive NK cell paucity and dysfunction in lung cancer
- Author
-
Matthew D. Park, Ivan Reyes-Torres, Jessica LeBerichel, Pauline Hamon, Nelson M. LaMarche, Samarth Hegde, Meriem Belabed, Leanna Troncoso, John A. Grout, Assaf Magen, Etienne Humblin, Achuth Nair, Martina Molgora, Jinchao Hou, Jenna H. Newman, Adam M. Farkas, Andrew M. Leader, Travis Dawson, Darwin D’Souza, Steven Hamel, Alfonso Rodriguez Sanchez-Paulete, Barbara Maier, Nina Bhardwaj, Jerome C. Martin, Alice O. Kamphorst, Ephraim Kenigsberg, Maria Casanova-Acebes, Amir Horowitz, Brian D. Brown, Lucas Ferrari De Andrade, Marco Colonna, Thomas U. Marron, and Miriam Merad
- Subjects
Immunology ,Immunology and Allergy - Published
- 2023
5. On the Biology and Therapeutic Modulation of Macrophages and Dendritic Cells in Cancer
- Author
-
Matthew D. Park, Meriem Belabed, Steven T. Chen, Pauline Hamon, Samarth Hegde, Raphaël Mattiuz, Thomas U. Marron, and Miriam Merad
- Subjects
Cancer Research ,Oncology ,Cell Biology - Abstract
Myeloid cells represent a dominant cellular compartment of tumor lesions and play key roles in tumor inception, progression, metastasis, and response to treatment. Mononuclear phagocytes (MNPs), which include dendritic cells and macrophages, are unique among myeloid cells, as they not only shape both the broader composition and state of the tumor microenvironment but can also specifically instruct cancer-specific, T cell–mediated tumor cell killing, making them especially attractive targets for cancer treatment. Although MNPs remain difficult to modulate therapeutically, our understanding of MNP biology in the antitumor immune response has expanded significantly, offering hope for new possibilities in cancer immunotherapy. Here, we review the recent advances in our study of the cellular identity, molecular diversity, and spatial organization of MNPs in tumors, and we discuss the importance of tailoring therapeutic strategies to incorporate these new insights into cancer treatment design.
- Published
- 2023
6. Abstract CT199: Rescuing response to ICI by blocking the type-2 immune axis in patients with NSCLC progressing on immunotherapy: A phase 1b/2 trial of dupilumab administered with checkpoint blockade
- Author
-
Thomas Urban Marron, Nelson M. LaMarche, Matthew D. Park, Samarth Hegde, Bailey Fitzgerald, Clotilde Hennequin, Raphael Mattiuz, Meriem Belabed, Jessica Le Berichel, Barbara Maier, Nicole Hall, Justin Miller, Deborah B. Doroshow, Nicholas Rohs, Rajwanth Veluswamy, Nicholas Venturini, Jorge E. Gomez, Christian Rolfo, David Yankelevitz, Udit Chaddha, Timothy Harkin, Mary B. Beasley, Seunghee Kim-schulze, Sacha Gnjatic, Fred R. Hirsch, and Miriam Merad
- Subjects
Cancer Research ,Oncology - Abstract
Type-2 cytokines are hypothesized to promote an immune-permissive milieu for cancer to grow. Through scRNAseq and CITEseq on human non-small cell lung cancer (NSCLC) and the krasG12Dp53−/− lung cancer model we previously described a tumor-enriched dendritic cell program of concomitant immunosuppression and activation which we termed the “mregDC,” that was also notable for a strong Th2 immune signature. We subsequently blocked the canonical Th2 cytokine IL-4 in vivo in tumor-bearing mice, and found that this significantly decreased lung tumor burden, which was recapitulated in multiple other tumor models. Furthermore, this effect synergized with PD-L1 blockade. Based on this data, we designed a clinical trial to assess if the addition of dupilumab, an anti-IL-4Ra antibody widely used for treatment of atopic diseases, may rescue responses to checkpoint blockade (NCT05013450). In this Phase 1b/2 trial, up to 21 patients with NSCLC that have progressed on prior anti-PD-(L)1 therapy will be enrolled. Patients continue PD-(L)1 blockade while receiving three doses of dupilumab, administered every three weeks, with initial radiographic assessment of response at 9 weeks. Patients without progression of disease then continue anti-PD-(L)1 alone. The primary endpoint of Phase 1b is safety and tolerability, while the primary endpoint of Phase 2, inclusive of patients from Phase 1b, is efficacy as per RECIST. Patients undergo pre- and on-treatment biopsies, pre-treatment stool collection for microbiome analysis, as well as blood collection at 6 timepoints for PBMCs, plasma and ctDNA. Here we report the Phase 1b portion that has completed accrual in which 6 patients were enrolled in a Phase 1b run-in to confirm safety and tolerability. There were no adverse events attributable to study treatment during Phase 1b in any of the 6 patients treated. Serum proteomic analysis of this cohort revealed that dupilumab treatment induced a profound increase in proinflammatory/tumoricidal immune effector molecules, and reversed a systemic Th2 cytokine signature. Furthermore, mass cytometry of circulating immune populations showed an expansion of cytotoxic lymphocyte populations and a reduction in immunosuppressive myeloid cells. The fourth patient treated on trial who had progressive disease after 9 cycles of consolidation checkpoint blockade following concurrent chemoradiation for squamous NSCLC was enrolled, and had a partial response at 9 weeks, with deepening of the PR at 25 weeks. This patient’s on-treatment biopsy showed a major increase in CD8 T cell tumor infiltration. Histological analysis using spatial transcriptomics and multiplexed imaging from these patients is ongoing, and will be reported at the conference. Based on this promising signal in the initial lead-in, the trial will proceed through Simon’s Two Stage design and enroll a full 21 patients as part of the Phase 2 expansion cohort. This clinical trial is funded entirely through philanthropy support through the Tisch Cancer Institute. Citation Format: Thomas Urban Marron, Nelson M. LaMarche, Matthew D. Park, Samarth Hegde, Bailey Fitzgerald, Clotilde Hennequin, Raphael Mattiuz, Meriem Belabed, Jessica Le Berichel, Barbara Maier, Nicole Hall, Justin Miller, Deborah B. Doroshow, Nicholas Rohs, Rajwanth Veluswamy, Nicholas Venturini, Jorge E. Gomez, Christian Rolfo, David Yankelevitz, Udit Chaddha, Timothy Harkin, Mary B. Beasley, Seunghee Kim-schulze, Sacha Gnjatic, Fred R. Hirsch, Miriam Merad. Rescuing response to ICI by blocking the type-2 immune axis in patients with NSCLC progressing on immunotherapy: A phase 1b/2 trial of dupilumab administered with checkpoint blockade [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT199.
- Published
- 2023
7. MDSC: Markers, development, states, and unaddressed complexity
- Author
-
Andrew Leader, Samarth Hegde, and Miriam Merad
- Subjects
0301 basic medicine ,Myeloid ,Disease outcome ,T-Lymphocytes ,Immunology ,Context (language use) ,Biology ,Article ,law.invention ,03 medical and health sciences ,0302 clinical medicine ,law ,medicine ,Animals ,Humans ,Immunology and Allergy ,Myeloid Cells ,Extramural ,Myeloid-Derived Suppressor Cells ,030104 developmental biology ,Infectious Diseases ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Suppressor ,Neuroscience ,Biomarkers ,Signal Transduction - Abstract
Summary Myeloid-derived suppressor cells (MDSCs) are one of the most discussed biological entities in immunology. While the context and classification of this group of cells has evolved, MDSCs most commonly describe cells arising during chronic inflammation, especially late-stage cancers, and are defined by their T cell immunosuppressive functions. This MDSC concept has helped explain myeloid phenomena associated with disease outcome, but currently lacks clear definitions and a unifying framework across pathologies. Here, we propose such a framework to classify MDSCs as discrete cell states based on activation signals in myeloid populations leading to suppressive modes characterized by specific, measurable effects. Developing this level of knowledge of myeloid states across pathological conditions may ultimately transform how disparate diseases are grouped and treated.
- Published
- 2021
8. Intratumoral mregDC and CXCL13 T helper niches enable local differentiation of CD8 T cells following PD-1 blockade
- Author
-
Assaf Magen, Pauline Hamon, Nathalie Fiaschi, Leanna Troncoso, Etienne Humblin, Darwin D’souza, Travis Dawson, Matthew D. Park, Joel Kim, Steven Hamel, Mark Buckup, Christie Chang, Alexandra Tabachnikova, Hara Schwartz, Nausicaa Malissen, Yonit Lavin, Alessandra Soares-Schanoski, Bruno Giotti, Samarth Hegde, Raphaël Mattiuz, Clotilde Hennequin, Jessica Le Berichel, Zhen Zhao, Stephen Ward, Isabel Fiel, Colles Price, Nicolas Fernandez, Jiang He, Baijun Kou, Michael Dobosz, Lianjie Li, Christina Adler, Min Ni, Yi Wei, Wei Wang, Namita T. Gupta, Kunal Kundu, Kamil Cygan, Raquel P. Deering, Alex Tsankov, Seunghee Kim-Schulze, Sacha Gnjatic, Ephraim Kenigsberg, Myron Schwartz, Thomas U. Marron, Gavin Thurston, Alice O. Kamphorst, and Miriam Merad
- Abstract
Here, we leveraged a large neoadjuvant PD-1 blockade trial in patients with hepatocellular carcinoma (HCC) to search for correlates of response to immune checkpoint blockade (ICB) within T cell-rich tumors. We show that ICB response correlated with the clonal expansion of intratumoral CXCL13+ CH25H+ IL-21+ PD-1+ CD4 T helper cells (CXCL13+ Th) and Granzyme K+ PD-1+ effector-like CD8 T cells, whereas terminally exhausted CD39hi TOXhi PD-1hi CD8 T cells dominated in non-responders. Strikingly, most T cell receptor (TCR) clones that expanded post-treatment were found in pre-treatment biopsies. Notably, PD-1+ TCF-1+ progenitor-like CD8 T cells were present in tumors of responders and non-responders and shared clones mainly with effector-like cells in responders or terminally differentiated cells in non-responders, suggesting that local CD8 T cell differentiation occurs upon ICB. We found that these progenitor CD8 T cells interact with CXCL13+ Th cells within cellular triads around dendritic cells enriched in maturation and regulatory molecules, or “mregDC”. Receptor-ligand analysis revealed unique interactions within these triads that may promote the differentiation of progenitor CD8 T cells into effector-like cells upon ICB. These results suggest that discrete intratumoral niches that include mregDC and CXCL13+ Th cells control the differentiation of tumor-specific progenitor CD8 T cell clones in patients treated with ICB.
- Published
- 2022
9. Pancreatic Cancer Immuno-oncology in the Era of Precision Medicine
- Author
-
Samarth Hegde
- Subjects
Oncology ,medicine.medical_specialty ,Tumor microenvironment ,endocrine system diseases ,business.industry ,medicine.medical_treatment ,Cancer ,Translational research ,Review Article ,Precision medicine ,medicine.disease ,Targeted therapy ,03 medical and health sciences ,0302 clinical medicine ,Surgical oncology ,Pancreatic tumor ,030220 oncology & carcinogenesis ,Internal medicine ,Pancreatic cancer ,medicine ,030211 gastroenterology & hepatology ,Surgery ,business - Abstract
Pancreatic malignancies carry a dismal prognosis globally, with pancreatic adenocarcinomas (PDAC) being particularly aggressive and stubborn. Unfortunately, several therapeutic strategies that show promise in other cancers have failed to make sizeable impact on pancreatic tumor outcomes. Responses to immunotherapies are especially rare in pancreatic cancer, and patients are in need of innovative approaches that can result in more durable responses. Current research in preclinical models and humans has suggested this resistance is due to a uniquely inflammatory and dysfunctional tumor microenvironment; these findings lay the groundwork for targeting these barriers and improving outcomes. Clinical analyses have also revealed unprecedented heterogeneity in tumor and stromal biology of PDAC, underscoring the need for more personalized approaches and combinatorial therapies. This review will highlight the current state of translational research focusing on PDAC immunity, summarize ongoing clinical efforts to tackle PDAC vulnerabilities, and underscore some unresolved challenges in implementing therapies more broadly. A better understanding of immune contexture and tumor heterogeneity in this disease will greatly accelerate drug discovery and implementation of precision medicine for PDAC.
- Published
- 2020
10. A phase 1b/2 trial of dupilumab given in conjunction with PD-(L)1 blockade in the treatment of relapsed/refractory metastatic NSCLC
- Author
-
Bailey Gleason Fitzgerald, Thomas Urban Marron, Nicole Hall, Daniel O'Grady, Nelson LaMarche, Clotilde Hennequin, Samarth Hegde, Barbara Maier, Jessica Le Berichel, Udit Chadda, Mary Beth Beasley, David F Yankelevitz, Jorge E. Gomez, Deborah Blythe Doroshow, Rajwanth Veluswamy, Nicholas Cole Rohs, Christian Diego Rolfo, Fred R. Hirsch, and Miriam Merad
- Subjects
Cancer Research ,Oncology - Abstract
TPS9139 Background: Although tumor microenvironments may contain chronic inflammatory cells, this milieu can lead to immune evasion and may contribute to resistance to immunotherapy. Dendritic cells are one of the most potent cross presenters of tumor antigen, and their function is crucial to tumor-directed adaptive immune responses. In the KP mouse model of lung adenocarcinoma (KrasG12D; Tp53-/-), we recently identified interleukin-4 (IL-4)-driven suppression of tumor-antigen charged dendritic cells, which was similarly seen in human lung cancer lesions (Maier, B., et al., A conserved dendritic-cell regulatory program limits antitumour immunity. Nature, 2020.580[7802]:257-262). In the mouse model IL-4 blockade resulted in an increase in IL-12, IFNg and TNF in CD8+ T cells and decreased tumor burden, and further antitumor activity was seen when combined with PD-L1 blockade. Dupilumab is a fully human monoclonal antibody that blocks the IL-4 receptor alpha subunit which disrupts signaling through receptors for both IL-4 and IL-13; it is FDA approved for patients with multiple atopic conditions, in whom series adverse effects are rare. Based on this pre-clinical data, we hypothesize that the addition of dupilumab to anti PD-(L)1 therapy will be well tolerated, and will rescue the anti-tumor effect of immune checkpoint blockade. Methods: This is a phase Ib/II trial. Patients with relapsed/refractory NSCLC who have received prior anti PD-(L)1 treatment are eligible for enrollment. In a phase Ib safety run-in, six patients will be enrolled in a modified set-dose 3+3 design. If no more than 1 DLT is observed during this phase, the trial will proceed to phase II. Phase II will enroll a further 15 patients in a minimax design with early stopping for futility to a maximum total of 21 patients. Patients will undergo pre-treatment biopsies and peripheral blood sampling prior to receiving 3 doses of dupilumab, administered every three weeks, in conjunction with continuing standard-of-care anti-PD-(L)1 therapy. Patients will undergo repeat biopsies 4 weeks after starting therapy. After completion of dupilumab (at 9 weeks) patients will undergo repeat staging. The primary endpoint of phase 1b is safety as measured by frequency and severity of adverse effects. The primary endpoint of phase II is overall response rate as assessed using RECIST 1.1 criteria at the time of post-dupilumab imaging. Exploratory endpoints include analysis of peripheral blood by CyTOF and O-link, and tissue biopsies will be analyzed by multiplex-IHC and bulk-RNA-sequencing. T cell receptor sequencing will be performed on tumor and matched peripheral blood samples, and circulating tumor DNA will be assessed at multiple time points. Phase 1b is currently enrolling as planned. Clinical trial information: NCT05013450.
- Published
- 2022
11. TREM2 Sensing of Tumor Cell Efferocytosis Promotes a Macrophage Molecular State that Limits NK Cell Antitumor Immunity
- Author
-
Steven Hamel, Matthew Park, Thomas U. Marron, Ephraim Kenigsberg, Alfonso Rodriguez Sanchez-Paulete, Leanna Troncoso, Maria Acebes-Casanova, Alice O. Kamphorst, Miriam Merad, John Grout, Travis Dawson, Assaf Magen, Barbara Maier, Etienne Humblin, Ivan Reyes-Torres, Pauline Hamon, Jessica Le Berichel, Brian D. Brown, Andrew Leader, Jerome Martin, Nelson L. Lamarche, Achuth Nair, and Samarth Hegde
- Subjects
History ,Polymers and Plastics ,Chemistry ,TREM2 ,medicine.medical_treatment ,Cell ,Immunosuppression ,medicine.disease ,Industrial and Manufacturing Engineering ,medicine.anatomical_structure ,Immune system ,Cancer research ,medicine ,Macrophage ,Bone marrow ,Business and International Management ,Efferocytosis ,Lung cancer - Abstract
Macrophages (MΦ) form a highly heterogenous compartment within tumor lesions. Using lineage tracing, we recently established that advanced NSCLC lesions in both mice and humans are depleted of tissue-resident macrophages (TRM) and are mainly populated by monocyte-derived MΦ (MoMΦ). Here, we show that TREM2+ MoMΦ dominate murine and human NSCLC lesions. Importantly, using mice reconstituted with mixed TREM2-deficient and -proficient bone marrow cells, we identified a cell-intrinsic ability for TREM2 to drive an efferocytosis-associated molecular program that profoundly reduced the expression of immunogenic molecules in tumor-infiltrating MoMΦ. Trem2 deletion significantly dampened this program, reversed MoMΦ immunosuppression, and significantly enhanced the accumulation of activated NK cells and cDC1 in tumor lesions. Notably, Trem2 deletion reduced lung cancer progression in an NK cell-dependent manner. Taken together, our results underscore the potential for therapeutic inhibition of TREM2 to mount a potent anti-tumor immune response by unleashing cooperative NK/cDC1 cell function.
- Published
- 2021
12. Many paths to COVID-19 lymphocyte dysfunction
- Author
-
Samarth Hegde
- Subjects
History ,2019-20 coronavirus outbreak ,medicine.anatomical_structure ,Coronavirus disease 2019 (COVID-19) ,SARS-CoV-2 ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Lymphocyte ,medicine ,Biology ,Virology ,In Brief ,Computer Science Applications ,Education - Published
- 2020
- Full Text
- View/download PDF
13. Immunology of COVID-19: current state of the science
- Author
-
Ephraim Kenigsberg, Joan Shang, Jovani Catalan, Tamar Plitt, Dan Fu Ruan, Katherine E. Lindblad, Jamie Redes, Francesca Cossarini, Zeynep H. Gümüş, Maria Casanova-Acebes, Julio A. Aguirre-Ghiso, Nina Bhardwaj, Robert M. Samstein, Venu Pothula, Uri Laserson, Matthew Lin, Erica Dalla, Jeremiah J. Faith, Manasi Agrawal, Alice O. Kamphorst, Ivan Reyes Torres, Luisanna Pia, Monica Centa, Jessica Tan, Brian D. Brown, Jonathan Chung, Graham J. Britton, Miriam Saffern, Assaf Magen, Matthew P. Spindler, Conor Gruber, Saurabh Mehandru, Amir Horowitz, Timothy O'Donnell, Florian Krammer, Jill Gregory, Gabrielle Lubitz, Pauline Hamon, Meriem Belabed, Matthew Brown, Emma Risson, Louise Malle, Emilie K. Grasset, Alfonso R. Sanchez-Paulete, Justine Noel, Zafar Mahmood, Daniel Lozano-Ojalvo, Mark P. Roberto, Julia Kodysh, Verena van der Heide, Evan Cody, Elliot Meritt, Chang Moon, Maria Suprun, Andrew Leader, Bérengère Salomé, Nicolas F. Fernandez, Dusan Bogunovic, Michelle Tran, Nicolas Vabret, Dirk Homann, Miyo Ota, Cansu Cimen Bozkus, Andrew Charap, Divya Jha, Konstantina Alexandropoulos, Etienne Humblin, Benjamin Greenbaum, Maria Kuksin, Gustavo Martinez-Delgado, Andrew K Chan, Myvizhi Esai Selvan, C. Matthias Wilk, Maria A. Curotto de Lafaille, Samarth Hegde, Alessandra Soares Schanoski, Joel Kim, Jaime Mateus-Tique, Alvaro Moreira, John A. Grout, Rachel Levantovsky, Natalie Vaninov, Peter S. Heeger, Mark Aleynick, Matthew D. Park, Judy H. Cho, Miriam Merad, and Steven T. Chen
- Subjects
2019-20 coronavirus outbreak ,Coronavirus disease 2019 (COVID-19) ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,viruses ,Immunology ,virus diseases ,Biology ,Article ,Infectious Diseases ,Immunology and Allergy ,Engineering ethics ,State of the science ,Current (fluid) ,Viral immunology ,Immunologic memory ,Coronavirus Infections - Abstract
The coronavirus disease 2019 (COVID-19) pandemic, caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has affected millions of people worldwide, igniting an unprecedented effort from the scientific community to understand the biological underpinning of COVID19 pathophysiology. In this review, we summarize the current state of knowledge of innate and adaptive immune responses elicited by SARS-CoV-2 infection and the immunological pathways that likely contribute to disease severity and death. We also discuss the rationale and clinical outcome of current therapeutic strategies as well as prospective clinical trials to prevent or treat SARS-CoV-2 infection.
- Published
- 2020
14. Does asthma make COVID-19 worse?
- Author
-
Samarth Hegde
- Subjects
History ,2019-20 coronavirus outbreak ,medicine.medical_specialty ,Coronavirus disease 2019 (COVID-19) ,business.industry ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,MEDLINE ,medicine.disease ,Computer Science Applications ,Education ,Internal medicine ,medicine ,business ,Asthma - Published
- 2020
15. Dendritic cell paucity leads to dysfunctional immune surveillance in pancreatic cancer
- Author
-
Julie K. Schwarz, Graham D. Hogg, William G. Hawkins, Carl J. DeSelm, Cedric Mpoy, Kenneth M. Murphy, Brett H. Herzog, Varintra E. Krisnawan, Samarth Hegde, John M. Baer, Buck E. Rogers, David G. DeNardo, Katherine A. Alexander, Kyung Bae Lee, Marcus A. Breden, Chong Zuo, Brett L. Knolhoff, Jack P. Tang, and Ryan C. Fields
- Subjects
0301 basic medicine ,Cancer Research ,Lung Neoplasms ,endocrine system diseases ,medicine.medical_treatment ,Article ,Metastasis ,03 medical and health sciences ,0302 clinical medicine ,Pancreatic cancer ,Carcinoma, Non-Small-Cell Lung ,medicine ,Humans ,Lung cancer ,Immunologic Surveillance ,integumentary system ,business.industry ,Immunotherapy ,Dendritic cell ,Dendritic Cells ,medicine.disease ,digestive system diseases ,Pancreatic Neoplasms ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,Tumor progression ,030220 oncology & carcinogenesis ,Cancer research ,Adenocarcinoma ,Pancreas ,business - Abstract
Summary Here, we utilized spontaneous models of pancreatic and lung cancer to examine how neoantigenicity shapes tumor immunity and progression. As expected, neoantigen expression during lung adenocarcinoma development leads to T cell-mediated immunity and disease restraint. By contrast, neoantigen expression in pancreatic ductal adenocarcinoma (PDAC) results in exacerbation of a fibro-inflammatory microenvironment that drives disease progression and metastasis. Pathogenic TH17 responses are responsible for this neoantigen-induced tumor progression in PDAC. Underlying these divergent T cell responses in pancreas and lung cancer are differences in infiltrating conventional dendritic cells (cDCs). Overcoming cDC deficiency in early-stage PDAC leads to disease restraint, while restoration of cDC function in advanced PDAC restores tumor-restraining immunity and enhances responsiveness to radiation therapy.
- Published
- 2020
16. Tumor-associated fibrosis as a regulator of tumor immunity and response to immunotherapy
- Author
-
David G. DeNardo, Hong Jiang, and Samarth Hegde
- Subjects
0301 basic medicine ,Cancer Research ,medicine.medical_treatment ,Immunology ,Inflammation ,Biology ,Article ,Extracellular matrix ,03 medical and health sciences ,Fibrosis ,Immunity ,Neoplasms ,medicine ,Animals ,Humans ,Immunology and Allergy ,Pancreas ,Tumor microenvironment ,Immunotherapy ,Fibroblasts ,biochemical phenomena, metabolism, and nutrition ,medicine.disease ,Extracellular Matrix ,030104 developmental biology ,Oncology ,Tumor Escape ,Drug Resistance, Neoplasm ,Tumor progression ,medicine.symptom - Abstract
Tumor-associated fibrosis is characterized by unchecked pro-fibrotic and pro-inflammatory signaling. The components of fibrosis including significant numbers of cancer-associated fibroblasts, dense collagen deposition, and extracellular matrix stiffness, are well appreciated regulators of tumor progression but may also be critical regulators of immune surveillance. While this suggests that the efficacy of immunotherapy may be limited in highly fibrotic cancers like pancreas, it also suggests a therapeutic opportunity to target fibrosis in these tumor types to reawaken anti-tumor immunity. This review discusses the mechanisms by which fibrosis might subvert tumor immunity and how to overcome these mechanisms.
- Published
- 2017
17. Agonism of CD11b reprograms innate immunity to sensitize pancreatic cancer to immunotherapies
- Author
-
Buck E. Rogers, Xiaobo Li, Roheena Z. Panni, Brett L. Knolhoff, Marcus A. Breden, Ryan C. Fields, David G. DeNardo, Vineet Gupta, Varintra E. Krisnawan, Chong Zuo, Samia Q. Khan, Graham D. Hogg, William G. Hawkins, Samarth Hegde, John M. Herndon, and Julie K. Schwarz
- Subjects
Myeloid ,T-Lymphocytes ,medicine.medical_treatment ,Article ,Antigens, CD ,Pancreatic cancer ,medicine ,Animals ,Humans ,Myeloid Cells ,Agonism ,Neoplasm Metastasis ,Cell Proliferation ,CD11b Antigen ,Innate immune system ,Hepatology ,biology ,business.industry ,Cell growth ,Monocyte ,Gastroenterology ,General Medicine ,Dendritic cell ,Immunotherapy ,Macrophage Activation ,medicine.disease ,Survival Analysis ,Immunity, Innate ,Mice, Inbred C57BL ,Pancreatic Neoplasms ,Disease Models, Animal ,Treatment Outcome ,medicine.anatomical_structure ,Integrin alpha M ,Disease Progression ,biology.protein ,Cancer research ,Cytokines ,business ,Integrin alpha Chains ,Granulocytes ,Carcinoma, Pancreatic Ductal - Abstract
Although checkpoint immunotherapies have revolutionized the treatment of cancer, not all tumor types have seen substantial benefit. Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy in which very limited responses to immunotherapy have been observed. Extensive immunosuppressive myeloid cell infiltration in PDAC tissues has been postulated as a major mechanism of resistance to immunotherapy. Strategies concomitantly targeting monocyte or granulocyte trafficking or macrophage survival, in combination with checkpoint immunotherapies, have shown promise in preclinical studies, and these studies have transitioned into ongoing clinical trials for the treatment of pancreatic and other cancer types. However, compensatory actions by untargeted monocytes, granulocytes, and/or tissue resident macrophages may limit the therapeutic efficacy of such strategies. CD11b/CD18 is an integrin molecule that is highly expressed on the cell surface of these myeloid cell subsets and plays an important role in their trafficking and cellular functions in inflamed tissues. Here, we demonstrate that the partial activation of CD11b by a small-molecule agonist (ADH-503) leads to the repolarization of tumor-associated macrophages, reduction in the number of tumor-infiltrating immunosuppressive myeloid cells, and enhanced dendritic cell responses. These actions, in turn, improve antitumor T cell immunity and render checkpoint inhibitors effective in previously unresponsive PDAC models. These data demonstrate that molecular agonism of CD11b reprograms immunosuppressive myeloid cell responses and potentially bypasses the limitations of current clinical strategies to overcome resistance to immunotherapy.
- Published
- 2019
18. The development of resistance to FAK inhibition in pancreatic cancer is linked to stromal depletion
- Author
-
Hongmei Jiang, Ryan C. Fields, David G. DeNardo, Kian-Huat Lim, Xiuting Liu, Kyung Bae Lee, Brett L. Knolhoff, Samarth Hegde, Jonathan A. Pachter, and Hong Jiang
- Subjects
0301 basic medicine ,STAT3 Transcription Factor ,Stromal cell ,biology ,Chemistry ,Gastroenterology ,SMAD ,Transforming growth factor beta ,medicine.disease ,Article ,Pancreatic Neoplasms ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Pancreatic cancer ,TGF beta signaling pathway ,STAT protein ,medicine ,biology.protein ,Cancer research ,Tumor Microenvironment ,Humans ,Janus kinase ,STAT3 - Abstract
ObjectiveWe investigated how pancreatic cancer developed resistance to focal adhesion kinase (FAK) inhibition over time.DesignPancreatic ductal adenocarcinoma (PDAC) tumours from KPC mice (p48-CRE; LSL-KRasG12D/wt; p53flox/wt) treated with FAK inhibitor were analysed for the activation of a compensatory survival pathway in resistant tumours. We identified pathways involved in the regulation of signal transducer and activator of transcription 3 (STAT3) signalling on FAK inhibition by gene set enrichment analysis and verified these outcomes by RNA interference studies. We also tested combinatorial approaches targeting FAK and STAT3 in syngeneic transplantable mouse models of PDAC and KPC mice.ResultsIn KPC mice, the expression levels of phosphorylated STAT3 (pSTAT3) were increased in PDAC cells as they progressed on FAK inhibitor therapy. This progression corresponded to decreased collagen density, lowered numbers of SMA+ fibroblasts and downregulation of the transforming growth factor beta (TGF-β)/SMAD signalling pathway in FAK inhibitor-treated PDAC tumours. Furthermore, TGF-β production by fibroblasts in vitro drives repression of STAT3 signalling and enhanced responsiveness to FAK inhibitor therapy. Knockdown of SMAD3 in pancreatic cancer cells abolished the inhibitory effects of TGF-β on pSTAT3. We further found that tumour-intrinsic STAT3 regulates the durability of the antiproliferative activity of FAK inhibitor, and combinatorial targeting of FAK and Janus kinase/STAT3 act synergistically to suppress pancreatic cancer progression in mouse models.ConclusionStromal depletion by FAK inhibitor therapy leads to eventual treatment resistance through the activation of STAT3 signalling. These data suggest that, similar to tumour-targeted therapies, resistance mechanisms to therapies targeting stromal desmoplasia may be critical to treatment durability.
- Published
- 2019
19. Targeting focal adhesion kinase renders pancreatic cancers responsive to checkpoint immunotherapy
- Author
-
Andrea Wang-Gillam, Melissa A. Meyer, John M. Herndon, Brett L. Knolhoff, Yu Zhu, David T. Weaver, Hong Jiang, Jonathan A. Pachter, Timothy M. Nywening, William G. Hawkins, Irina M. Shapiro, Samarth Hegde, and David G. DeNardo
- Subjects
0301 basic medicine ,Antimetabolites, Antineoplastic ,endocrine system diseases ,medicine.medical_treatment ,Immunoblotting ,Programmed Cell Death 1 Receptor ,Aminopyridines ,CD8-Positive T-Lymphocytes ,Biology ,Deoxycytidine ,Immunotherapy, Adoptive ,General Biochemistry, Genetics and Molecular Biology ,Focal adhesion ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Tumor Microenvironment ,medicine ,Animals ,Humans ,Cytotoxic T cell ,Cell Proliferation ,Tumor microenvironment ,Reverse Transcriptase Polymerase Chain Reaction ,Cell growth ,General Medicine ,Immunotherapy ,Fibrosis ,Immunohistochemistry ,Gemcitabine ,digestive system diseases ,3. Good health ,Pancreatic Neoplasms ,Immunosurveillance ,Disease Models, Animal ,030104 developmental biology ,Tumor progression ,Focal Adhesion Protein-Tyrosine Kinases ,030220 oncology & carcinogenesis ,Disease Progression ,Cancer research ,Tumor Escape ,CD8 ,Carcinoma, Pancreatic Ductal - Abstract
Single-agent immunotherapy has achieved limited clinical benefit to date in patients with pancreatic ductal adenocarcinoma (PDAC). This may be a result of the presence of a uniquely immunosuppressive tumor microenvironment (TME). Critical obstacles to immunotherapy in PDAC tumors include a high number of tumor-associated immunosuppressive cells and a uniquely desmoplastic stroma that functions as a barrier to T cell infiltration. We identified hyperactivated focal adhesion kinase (FAK) activity in neoplastic PDAC cells as an important regulator of the fibrotic and immunosuppressive TME. We found that FAK activity was elevated in human PDAC tissues and correlated with high levels of fibrosis and poor CD8(+) cytotoxic T cell infiltration. Single-agent FAK inhibition using the selective FAK inhibitor VS-4718 substantially limited tumor progression, resulting in a doubling of survival in the p48-Cre;LSL-Kras(G12D);Trp53(flox/+) (KPC) mouse model of human PDAC. This delay in tumor progression was associated with markedly reduced tumor fibrosis and decreased numbers of tumor-infiltrating immunosuppressive cells. We also found that FAK inhibition rendered the previously unresponsive KPC mouse model responsive to T cell immunotherapy and PD-1 antagonists. These data suggest that FAK inhibition increases immune surveillance by overcoming the fibrotic and immunosuppressive PDAC TME and renders tumors responsive to immunotherapy.
- Published
- 2016
20. Low-barrier hydrogen bonds in proteins
- Author
-
Amit Das, Ramakrishna V. Hosur, R. Chitra, M. V. Hosur, Samarth Hegde, and R.R. Choudhury
- Subjects
biology ,Chemistry ,Hydrogen bond ,Low-barrier hydrogen bond ,Active site ,General Chemistry ,Hydrogen atom ,Condensed Matter Physics ,Biochemistry ,Small molecule ,Folding (chemistry) ,Crystallography ,Protein structure ,Structural Biology ,biology.protein ,General Materials Science ,Protein folding - Abstract
Hydrogen bonding interactions are one of the most important chemical interactions among materials, especially biological materials, which help confer specificity, which is crucial for their efficient functioning. Recently, low-barrier hydrogen bonds (LBHBs) have been proposed to play a critical role in enzyme catalysis. In this review, tools to identify LBHBs are described, along with analyses of neutron crystal structures of small molecules to identify geometric parameters characteristic of LBHBs, which are assumed to be characterized by dynamic disorder along the hydrogen bond (H-bond) of the bonding hydrogen atom. The analysis of protein structures determined by neutron diffraction indicates that LBHBs are found to occur in both active site and non-active site regions of a protein. Moreover, very short H-bonds are observed in the vicinity of folding cores identified through nuclear magnetic resonance studies on two proteins, SUMO-1 and HIV-1 protease. This observation suggests that LBHBs may also be im...
- Published
- 2013
21. A skin-depth analysis of integrins: role of the integrin network in health and disease
- Author
-
Srikala Raghavan and Samarth Hegde
- Subjects
Integrins ,Skin Neoplasms ,Angiogenesis ,Clinical Biochemistry ,Integrin ,Disease ,Biology ,medicine.disease_cause ,Skin Diseases ,medicine ,Cell Adhesion ,Animals ,Cell adhesion ,Skin ,Basement membrane ,integumentary system ,Cell Biology ,General Medicine ,Adhesion ,Hemidesmosomes ,Cell biology ,Extracellular Matrix ,medicine.anatomical_structure ,biology.protein ,Epidermis ,Carcinogenesis - Abstract
In the skin epidermis, adhesion to the underlying basement membrane is mediated through trans-membrane integrin receptors. In addition to a structural role, integrins can signal in a bi-directional manner though the membrane and thus play a crucial role in cell adhesion, migration, proliferation, and differentiation. In this review we will discuss the role of integrins and their network of partner proteins in normal skin development, and how dysregulation influences disease states such as skin blistering disorders and cancers. We also discuss major integrin-specific therapeutic advances that have been made over the past few years in treating these skin disorders as well as targeting angiogenesis, neo-vasculature, and tumorigenesis.
- Published
- 2013
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.