IU Indianapolis ScholarWorks :: Browsing by Author "Matosevic, Sandro"

Browsing by Author "Matosevic, Sandro"

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Engineered natural killer cells impede the immunometabolic CD73-adenosine axis in solid tumors
(eLife Sciences, 2022-07-11) Chambers, Andrea M.; Lupo, Kyle B.; Wang, Jiao; Cao, Jingming; Utturkar, Sagar; Lanman, Nadia; Bernal-Crespo, Victor; Jalal, Shadia; Pine, Sharon R.; Torregrosa-Allen, Sandra; Elzey, Bennett D.; Matosevic, Sandro; Medicine, School of Medicine
Immunometabolic reprogramming due to adenosine produced by CD73 (encoded by the 5'-ectonucleotidase gene NT5E) is a recognized immunosuppressive mechanism contributing to immune evasion in solid tumors. Adenosine is not only known to contribute to tumor progression, but it has specific roles in driving dysfunction of immune cells, including natural killer (NK) cells. Here, we engineered human NK cells to directly target the CD73-adenosine axis by blocking the enzymatic activity of CD73. In doing so, the engineered NK cells not only impaired adenosinergic metabolism driven by the hypoxic uptake of ATP by cancer cells in a model of non-small-cell lung cancer, but also mediated killing of tumor cells due to the specific recognition of overexpressed CD73. This resulted in a 'single agent' immunotherapy that combines antibody specificity, blockade of purinergic signaling, and killing of targets mediated by NK cells. We also showed that CD73-targeted NK cells are potent in vivo and result in tumor arrest, while promoting NK cell infiltration into CD73+ tumors and enhancing intratumoral activation.
Functional expression of CD73 on human natural killer cells
(Springer, 2022) Chambers, Andrea M.; Wang, Jiao; Dao, Tram N.; Lupo, Kyle B.; Veenhuis, Paige; Ayers, Mitchell G.; Slivova, Veronika; Cohen‑Gadol, Aaron A.; Matosevic, Sandro; Neurological Surgery, School of Medicine
The production of adenosine by CD73 on cancer cells in the tumor microenvironment is a recognized immunosuppressive mechanism contributing to immune evasion in many solid tumors. While NK cells have been purported to overexpress CD73 under certain conditions, this phenomenon has remained elusive and unclear. We have found that while NK cells are able to upregulate expression of CD73 on their surface when exposed to CD73+ cancer cells, this upregulation is not universal, nor is it often substantial. Rather, our data point to the extent of CD73 expression on NK cells to be both cancer-specific and environmentally-driven, and largely limited in intensity. We found that NK cell overexpression of CD73 responds to the level of CD73 on cancer cells and is enhanced in hypoxia. Interestingly, human CD73+ NK cells appear hyperfunctional in vitro compared to CD73- NK cells, suggesting that CD73 expression could be a bystander of NK cell activation. In addition, glioblastoma patient data show that tumor-infiltrating NK cells express CD73 variably, depending on donor, and present lower expression of CD16, alongside patient-specific changes in CEACAM1, CXCR3 and TIM-3, suggesting some functional changes in NK cell responses associated with expression of CD73 on NK cells in vivo. Taken together, our study is the first to show that while NK cells are largely resistant to the upregulation of CD73, CD73 expression is inducible on NK cells in response to CD73 on cancer cells, and these cells are associated with distinct functional signatures.
Functional expression of CD73 on human natural killer cells
(Springer, 2022-12) Chambers, Andrea M.; Wang, Jiao; Dao, Tram N.; Lupo, Kyle B.; Veenhuis, Paige; Ayers, Mitchell G.; Slivova, Veronika; Cohen-Gadol, Aaron A.; Matosevic, Sandro; Neurological Surgery, School of Medicine
The production of adenosine by CD73 on cancer cells in the tumor microenvironment is a recognized immunosuppressive mechanism contributing to immune evasion in many solid tumors. While NK cells have been purported to overexpress CD73 under certain conditions, this phenomenon has remained elusive and unclear. We have found that while NK cells are able to upregulate expression of CD73 on their surface when exposed to CD73+ cancer cells, this upregulation is not universal, nor is it often substantial. Rather, our data point to the extent of CD73 expression on NK cells to be both cancer-specific and environmentally-driven, and largely limited in intensity. We found that NK cell overexpression of CD73 responds to the level of CD73 on cancer cells and is enhanced in hypoxia. Interestingly, human CD73+ NK cells appear hyperfunctional in vitro compared to CD73− NK cells, suggesting that CD73 expression could be a bystander of NK cell activation. In addition, glioblastoma patient data show that tumor-infiltrating NK cells express CD73 variably, depending on donor, and present lower expression of CD16, alongside patient-specific changes in CEACAM1, CXCR3 and TIM-3, suggesting some functional changes in NK cell responses associated with expression of CD73 on NK cells in vivo. Taken together, our study is the first to show that while NK cells are largely resistant to the upregulation of CD73, CD73 expression is inducible on NK cells in response to CD73 on cancer cells, and these cells are associated with distinct functional signatures.
Functional expression of CD73 on human natural killer cells
(Springer, 2022) Chambers, Andrea M.; Wang, Jiao; Dao, Tram N.; Lupo, Kyle B.; Veenhuis, Paige; Ayers, Mitchell G.; Slivova, Veronika; Cohen‑Gadol, Aaron A.; Matosevic, Sandro; Neurological Surgery, School of Medicine
The production of adenosine by CD73 on cancer cells in the tumor microenvironment is a recognized immunosuppressive mechanism contributing to immune evasion in many solid tumors. While NK cells have been purported to overexpress CD73 under certain conditions, this phenomenon has remained elusive and unclear. We have found that while NK cells are able to upregulate expression of CD73 on their surface when exposed to CD73+ cancer cells, this upregulation is not universal, nor is it often substantial. Rather, our data point to the extent of CD73 expression on NK cells to be both cancer-specific and environmentally-driven, and largely limited in intensity. We found that NK cell overexpression of CD73 responds to the level of CD73 on cancer cells and is enhanced in hypoxia. Interestingly, human CD73+ NK cells appear hyperfunctional in vitro compared to CD73− NK cells, suggesting that CD73 expression could be a bystander of NK cell activation. In addition, glioblastoma patient data show that tumor-infiltrating NK cells express CD73 variably, depending on donor, and present lower expression of CD16, alongside patient-specific changes in CEACAM1, CXCR3 and TIM-3, suggesting some functional changes in NK cell responses associated with expression of CD73 on NK cells in vivo. Taken together, our study is the first to show that while NK cells are largely resistant to the upregulation of CD73, CD73 expression is inducible on NK cells in response to CD73 on cancer cells, and these cells are associated with distinct functional signatures.
Immunotherapy in Lung Cancer: Current Landscape and Future Directions
(Frontiers, 2022-02-08) Mamdani, Hirva; Matosevic, Sandro; Khalid, Ahmed Bilal; Durm, Gregory; Jalal, Shadia I.; Medicine, School of Medicine
Over the past decade, lung cancer treatment has undergone a major paradigm shift. A greater understanding of lung cancer biology has led to the development of many effective targeted therapies as well as of immunotherapy. Immune checkpoint inhibitors (ICIs) have shown tremendous benefit in the treatment of non-small cell lung cancer (NSCLC) and are now being used as first-line therapies in metastatic disease, consolidation therapy following chemoradiation in unresectable locally advanced disease, and adjuvant therapy following surgical resection and chemotherapy in resectable disease. Despite these benefits, predicting who will respond to ICIs has proven to be difficult and there remains a need to discover new predictive immunotherapy biomarkers. Furthermore, resistance to ICIs in lung cancer is frequent either because of a lack of response or disease progression after an initial response. The utility of ICIs in the treatment of small cell lung cancer (SCLC) remains limited to first-line treatment of extensive stage disease in combination with chemotherapy with modest impact on overall survival. It is thus important to explore and exploit additional targets to reap the full benefits of immunotherapy in the treatment of lung cancer. Here, we will summarize the current state of immunotherapy in lung cancer, discuss novel targets, and explore the intersection between DNA repair defects and immunotherapy.
Multispecific targeting of glioblastoma with tumor microenvironment-responsive multifunctional engineered NK cells
(National Academy of Science, 2021) Wang, Jiao; Toregrosa-Allen, Sandra; Elzey, Bennett D.; Utturkar, Sagar; Lanman, Nadia Atallah; Bernal-Crespo, Victor; Behymer, Matthew M.; Knipp, Gregory T.; Yun, Yeonhee; Veronesi, Michael C.; Sinn, Anthony L.; Pollok, Karen E.; Brutkiewicz, Randy R.; Nevel, Kathryn S.; Matosevic, Sandro; Radiology and Imaging Sciences, School of Medicine
Tumor antigen heterogeneity, a severely immunosuppressive tumor microenvironment (TME) and lymphopenia resulting in inadequate immune intratumoral trafficking, have rendered glioblastoma (GBM) highly resistant to therapy. To address these obstacles, here we describe a unique, sophisticated combinatorial platform for GBM: a cooperative multifunctional immunotherapy based on genetically engineered human natural killer (NK) cells bearing multiple antitumor functions including local tumor responsiveness that addresses key drivers of GBM resistance to therapy: antigen escape, immunometabolic reprogramming of immune responses, and poor immune cell homing. We engineered dual-specific chimeric antigen receptor (CAR) NK cells to bear a third functional moiety that is activated in the GBM TME and addresses immunometabolic suppression of NK cell function: a tumor-specific, locally released antibody fragment which can inhibit the activity of CD73 independently of CAR signaling and decrease the local concentration of adenosine. The multifunctional human NK cells targeted patient-derived GBM xenografts, demonstrated local tumor site-specific activity in the tissue, and potently suppressed adenosine production. We also unveil a complex reorganization of the immunological profile of GBM induced by inhibiting autophagy. Pharmacologic impairment of the autophagic process not only sensitized GBM to antigenic targeting by NK cells but promoted a chemotactic profile favorable to NK infiltration. Taken together, our study demonstrates a promising NK cell-based combinatorial strategy that can target multiple clinically recognized mechanisms of GBM progression simultaneously.
Rora Regulates Neutrophil Migration and Activation in Zebrafish
(Frontiers Media, 2022-03-04) Hsu, Alan Y.; Wang, Tianqi; Syahirah, Ramizah; Liu, Sheng; Li, Kailing; Zhang, Weiwei; Wang, Jiao; Cao, Ziming; Tian, Simon; Matosevic, Sandro; Staiger, Christopher J.; Wan, Jun; Deng, Qing; Medical and Molecular Genetics, School of Medicine
Neutrophil migration and activation are essential for defense against pathogens. However, this process may also lead to collateral tissue injury. We used microRNA overexpression as a platform and discovered protein-coding genes that regulate neutrophil migration. Here we show that miR-99 decreased the chemotaxis of zebrafish neutrophils and human neutrophil-like cells. In zebrafish neutrophils, miR-99 directly targets the transcriptional factor RAR-related orphan receptor alpha (roraa). Inhibiting RORα, but not the closely related RORγ, reduced chemotaxis of zebrafish and primary human neutrophils without causing cell death, and increased susceptibility of zebrafish to bacterial infection. Expressing a dominant-negative form of Rorα or disrupting the roraa locus specifically in zebrafish neutrophils reduced cell migration. At the transcriptional level, RORα regulates transmembrane signaling receptor activity and protein phosphorylation pathways. Our results, therefore, reveal previously unknown functions of miR-99 and RORα in regulating neutrophil migration and anti-microbial defense.
TIGIT contributes to the regulation of 4-1BB and does not define NK cell dysfunction in glioblastoma
(Elsevier, 2023-10-28) Lupo, Kyle B.; Torregrosa-Allen, Sandra; Elzey, Bennett D.; Utturkar, Sagar; Lanman, Nadia A.; Cohen-Gadol, Aaron A.; Slivova, Veronika; McIntosh, MacKenzie; Pollok, Karen E.; Matosevic, Sandro; Urology, School of Medicine
TIGIT is a receptor on human natural killer (NK) cells. Here, we report that TIGIT does not spontaneously induce inhibition of NK cells in glioblastoma (GBM), but rather acts as a decoy-like receptor, by usurping binding partners and regulating expression of NK activating ligands and receptors. Our data show that in GBM patients, one of the underpinnings of unresponsiveness to TIGIT blockade is that by targeting TIGIT, NK cells do not lose an inhibitory signal, but gains the potential for new interactions with other, shared, TIGIT ligands. Therefore, TIGIT does not define NK cell dysfunction in GBM. Further, in GBM, TIGIT+ NK cells are hyperfunctional. In addition, we discovered that 4-1BB correlates with TIGIT expression, the agonism of which contributes to TIGIT immunotherapy. Overall, our data suggest that in GBM, TIGIT acts as a regulator of a complex network, and provide new clues about its use as an immunotherapeutic target.
Tumor-responsive, multifunctional CAR-NK cells cooperate with impaired autophagy to infiltrate and target glioblastoma
(bioRxiv, 2020) Wang, Jiao; Toregrosa-Allen, Sandra; Elzey, Bennett D.; Utturkar, Sagar; Lanman, Nadia Atallah; Bernal-Crespo, Victor; Behymer, Matthew M.; Knipp, Gregory T.; Yun, Yeonhee; Veronesi, Michael C.; Sinn, Anthony L.; Pollok, Karen E.; Brutkiewicz, Randy R.; Nevel, Kathryn S.; Matosevic, Sandro; Radiology and Imaging Sciences, School of Medicine
Tumor antigen heterogeneity, a severely immunosuppressive tumor microenvironment (TME) and lymphopenia resulting in inadequate immune intratumoral trafficking have rendered glioblastoma (GBM) highly resistant to therapy. As a result, GBM immunotherapies have failed to demonstrate sustained clinical improvements in patient overall survival (OS). To overcome these obstacles, here we describe a novel, sophisticated combinatorial platform for GBM: the first multifunctional immunotherapy based on genetically-engineered, human NK cells bearing multiple anti-tumor functions, including local tumor responsiveness, that addresses key drivers of GBM resistance to therapy: antigen escape, poor immune cell homing, and immunometabolic reprogramming of immune responses. We engineered dual-specific CAR-NK cells to bear a third functional moiety that is activated in the GBM TME and addresses immunometabolic suppression of NK cell function: a tumor-specific, locally-released antibody fragment which can inhibit the activity of CD73 independently of CAR signaling and decrease the local concentration of adenosine. The multifunctional human NK cells targeted patient-derived GBM xenografts, demonstrated local tumor site specific activity in the tissue and potently suppressed adenosine production. We also unveil a complex reorganization of the immunological profile of GBM induced by inhibiting autophagy. Pharmacologic impairment of the autophagic process not only sensitized GBM to antigenic targeting by NK cells, but promoted a chemotactic profile favorable to NK infiltration. Taken together, our study demonstrates a promising new NK cell-based combinatorial strategy that can target multiple clinically-recognized mechanisms of GBM progression simultaneously.

Browsing by Author "Matosevic, Sandro"

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