scholarly journals Interactions Between Anti-Angiogenic Therapy and Immunotherapy in Glioblastoma

2022 ◽  
Vol 11 ◽  
Author(s):  
Saket Jain ◽  
Eric J. Chalif ◽  
Manish K. Aghi
Keyword(s):  
Tumor Microenvironment ◽  
Immune Cells ◽  
Randomized Clinical Trials ◽  
Neutralizing Antibody ◽  
Tumor Vasculature ◽  
Tumor Evolution ◽  
Therapeutic Modalities ◽  
Angiogenic Therapy ◽  
T Cell Infiltration ◽  
Immunosuppressive Microenvironment

Glioblastoma is the most aggressive brain tumor with a median survival ranging from 6.2 to 16.7 months. The complex interactions between the tumor and the cells of tumor microenvironment leads to tumor evolution which ultimately results in treatment failure. Immunotherapy has shown great potential in the treatment of solid tumors but has been less effective in treating glioblastoma. Failure of immunotherapy in glioblastoma has been attributed to low T-cell infiltration in glioblastoma and dysfunction of the T-cells that are present in the glioblastoma microenvironment. Recent advances in single-cell sequencing have increased our understanding of the transcriptional changes in the tumor microenvironment pre and post-treatment. Another treatment modality targeting the tumor microenvironment that has failed in glioblastoma has been anti-angiogenic therapy such as the VEGF neutralizing antibody bevacizumab, which did not improve survival in randomized clinical trials. Interestingly, the immunosuppressed microenvironment and abnormal vasculature of glioblastoma interact in ways that suggest the potential for synergy between these two therapeutic modalities that have failed individually. Abnormal tumor vasculature has been associated with immune evasion and the creation of an immunosuppressive microenvironment, suggesting that inhibiting pro-angiogenic factors like VEGF can increase infiltration of effector immune cells into the tumor microenvironment. Remodeling of the tumor vasculature by inhibiting VEGFR2 has also been shown to improve the efficacy of PDL1 cancer immunotherapy in mouse models of different cancers. In this review, we discuss the recent developments in our understanding of the glioblastoma tumor microenvironment specially the tumor vasculature and its interactions with the immune cells, and opportunities to target these interactions therapeutically. Combining anti-angiogenic and immunotherapy in glioblastoma has the potential to unlock these therapeutic modalities and impact the survival of patients with this devastating cancer.

scholarly journals 730 Hypoxia reduction in tandem with anti-angiogenic therapy remodels the PDAC microenvironment and potentiates CD40 agonist therapy

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A759-A759
Author(s):  
Arthur Liu ◽  
Michael Curran
Keyword(s):  
Prostate Cancer ◽  
Pancreatic Cancer ◽  
T Cell ◽  
Tumor Microenvironment ◽  
Cell Function ◽  
Tumor Vasculature ◽  
Cd8 T Cell ◽  
Agonist Therapy ◽  
Angiogenic Therapy ◽  
T Cell Infiltration

BackgroundThe majority of patients with pancreatic ductal adenocarcinoma (PDAC) fail to derive any durable responses from single agent immune checkpoint blockade therapy. This refractory state originates from PDAC's unique tumor microenvironment that is densely populated by immunosuppressive myeloid cells while excluding most antitumor CD8 T cells.1 In addition, PDAC is highly hypoxic and exhibits poor vascularity, both qualities which further limit antitumor immunity.2 3 We showed that the hypoxia-activated prodrug TH-302 (Evofosfamide) potentiates immunotherapy responses.4 Mechanistically, TH-302 decreases intratumoral hypoxia and initiates normalization of the tumor vasculature. While TH-302 facilitates a cellular remodeling process that diminishes tumor hypoxia, the nature of the vascular remodeling involved remains unknown, as do the downstream consequences for the composition of the tumor microenvironment and responsiveness to immunotherapy. We hypothesized that anti-angiogenic therapy and Evofosfamide might cooperate to normalize tumor vasculature and diminish hypoxia.MethodsTH-302 and a vascular endothelial growth factor receptor-2 (VEGFR-2) blocking antibody were used to treat several syngeneic murine models, including orthotopic pancreatic cancer and a transplantable model of prostate cancer. Immunofluorescence and flow cytometry were used to assess intratumoral hypoxia, vessel normalization, and tumor immune infiltrate.ResultsWe find that anti-VEGFR-2 (DC101) in combination with TH-302 demonstrates a cooperative benefit to combat both orthotopically implanted pancreatic cancer and transplantable prostate cancer. Combination therapy reduces intratumoral hypoxia, leads to pruning of the tumor vasculature, and increases the infiltration of endothelial cells into hypoxic regions. Across models, the combination of DC101 and TH-302 significantly enhance CD8 T cell function and limits their exhausted state. At the same time, tumor associated macrophages exhibit decreased expression of M2-like features. Similar to other anti-angiogenic therapies, combination DC101 and TH-302 leads to an increased frequency of PD-L1 expressing cells. Concurrent anti-PD-1 failed to provide any additional therapeutic benefit, which in part may be due poor CD8 T cell infiltration. Instead, we find that CD40 agonist therapy is improved when combined with TH-302 and DC101.ConclusionsTH-302 and DC101 utilize unique yet complementary mechanisms to improve the survival of mice challenged with pancreatic or prostate tumors. This combination relieves hypoxia and simultaneously reinvigorates T cell function and reduces macrophage mediated immunosuppression. In this setting, CD40 agonist therapy provides an additive benefit in prolonging mouse survival. Put together, these data indicate that targeted hypoxia reduction with anti-angiogenic therapy remodels the tumor microenvironment and enhances immunotherapy responses in PDAC.ReferencesBear AS, Vonderheide RH, O'Hara MH. Challenges and opportunities for pancreatic cancer immunotherapy. Cancer Cell. 2020;38(6):788–802. doi: 10.1016/j.ccell.2020.08.004. Epub 2020 Sep 17. PMID: 32946773; PMCID: PMC7738380.Koong AC, Mehta VK, Le QT, Fisher GA, Terris DJ, Brown JM, Bastidas AJ, Vierra M. Pancreatic tumors show high levels of hypoxia. Int J Radiat Oncol Biol Phys 2000;48(4):919–22. doi: 10.1016/s0360-3016(00)00803-8. PMID: 11072146.Olive KP, Jacobetz MA, Davidson CJ, Gopinathan A, McIntyre D, Honess D, Madhu B, Goldgraben MA, Caldwell ME, Allard D, Frese KK, Denicola G, Feig C, Combs C, Winter SP, Ireland-Zecchini H, Reichelt S, Howat WJ, Chang A, Dhara M, Wang L, Rückert F, Grützmann R, Pilarsky C, Izeradjene K, Hingorani SR, Huang P, Davies SE, Plunkett W, Egorin M, Hruban RH, Whitebread N, McGovern K, Adams J, Iacobuzio-Donahue C, Griffiths J, Tuveson DA. Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science 2009;324(5933):1457–61. doi: 10.1126/science.1171362. Epub 2009 May 21. PMID: 19460966; PMCID: PMC2998180.Jayaprakash P, Ai M, Liu A, Budhani P, Bartkowiak T, Sheng J, Ager C, Nicholas C, Jaiswal AR, Sun Y, Shah K, Balasubramanyam S, Li N, Wang G, Ning J, Zal A, Zal T, Curran MA. Targeted hypoxia reduction restores T cell infiltration and sensitizes prostate cancer to immunotherapy. J Clin Invest 2018;128(11):5137–5149. doi: 10.1172/JCI96268. Epub 2018 Oct 15. PMID: 30188869; PMCID: PMC6205399.

scholarly journals Role of Regular Physical Exercise in Tumor Vasculature: Favorable Modulator of Tumor Milieu

2020 ◽  
Author(s):  
Mário Esteves ◽  
Mariana P. Monteiro ◽  
Jose Alberto Duarte
Keyword(s):  
Tumor Microenvironment ◽  
Physical Exercise ◽  
Immune Cells ◽  
Fluid Pressure ◽  
Tumor Development ◽  
Tumor Vasculature ◽  
Vascular Conductance ◽  
Transient Nature ◽  
Underlying Mechanisms ◽  
Regular Physical Exercise

AbstractThe tumor vessel network has been investigated as a precursor of an inhospitable tumor microenvironment, including its repercussions in tumor perfusion, oxygenation, interstitial fluid pressure, pH, and immune response. Dysfunctional tumor vasculature leads to the extravasation of blood to the interstitial space, hindering proper perfusion and causing interstitial hypertension. Consequently, the inadequate delivery of oxygen and clearance of by-products of metabolism promote the development of intratumoral hypoxia and acidification, hampering the action of immune cells and resulting in more aggressive tumors. Thus, pharmacological strategies targeting tumor vasculature were developed, but the overall outcome was not satisfactory due to its transient nature and the higher risk of hypoxia and metastasis. Therefore, physical exercise emerged as a potential favorable modulator of tumor vasculature, improving intratumoral vascularization and perfusion. Indeed, it seems that regular exercise practice is associated with lasting tumor vascular maturity, reduced vascular resistance, and increased vascular conductance. Higher vascular conductance reduces intratumoral hypoxia and increases the accessibility of circulating immune cells to the tumor milieu, inhibiting tumor development and improving cancer treatment. The present paper describes the implications of abnormal vasculature on the tumor microenvironment and the underlying mechanisms promoted by regular physical exercise for the re-establishment of more physiological tumor vasculature.

Study of Tumor Microenvironment to Vascular Normalization Based on 3-D Simulation of Tumor Haemodynamics

2009 ◽  
Author(s):  
Jie Wu ◽  
Shixiong Xu ◽  
Quan Long
Keyword(s):  
Experimental Data ◽  
Tumor Microenvironment ◽  
Transport Properties ◽  
Experimental Studies ◽  
Tumor Vasculature ◽  
Clinical Settings ◽  
Vascular Normalization ◽  
Angiogenic Therapy

In recent years, anti-angiogenic therapy has been extensively studied in both preclinical and clinical settings. Experimental studies have approved its effects on the normalization of tumor vasculature as well as the microenvironment in tumors [1]. However, little is known about how tumor microenvironment is affected by the changes in structure of vasculature or transport properties of vessels and interstitium that are associated with anti-angiogenic therapy, since the experimental data are difficult to obtain [2].

scholarly journals Glioblastoma: Relationship between Metabolism and Immunosuppressive Microenvironment

Cells ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 3529
Author(s):  
Ainhoa Hernández ◽  
Marta Domènech ◽  
Ana M. Muñoz-Mármol ◽  
Cristina Carrato ◽  
Carmen Balana
Keyword(s):  
Brain Tumor ◽  
Tumor Microenvironment ◽  
Treatment Response ◽  
Immune Cells ◽  
Genetic Alterations ◽  
Tumor Initiation ◽  
Immunosuppressive Microenvironment

Glioblastoma (GBM) is the most aggressive brain tumor in adults and is characterized by an immunosuppressive microenvironment. Different factors shaping this tumor microenvironment (TME) regulate tumor initiation, progression, and treatment response. Genetic alterations and metabolism pathways are two main elements that influence tumor immune cells and TME. In this manuscript, we review how both factors can contribute to an immunosuppressive state and overview the strategies being tested.

scholarly journals c-Cbl targets PD-1 in immune cells for proteasomal degradation and modulates colorectal tumor growth

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Chimera Lyle ◽  
Sean Richards ◽  
Kei Yasuda ◽  
Marc Arthur Napoleon ◽  
Joshua Walker ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Immune Cells ◽  
Immune Checkpoint ◽  
Ring Finger ◽  
Neutralizing Antibody ◽  
Proteasomal Degradation ◽  
Negative Regulator ◽  
C Terminus ◽  
Fold Reduction ◽  
Programmed Cell Death 1

AbstractCasitas B lymphoma (c-Cbl) is an E3 ubiquitin ligase and a negative regulator of colorectal cancer (CRC). Despite its high expression in immune cells, the effect of c-Cbl on the tumor microenvironment remains poorly understood. Here we demonstrate that c-Cbl alters the tumor microenvironment and suppresses Programmed cell death-1 (PD-1) protein, an immune checkpoint receptor. Using syngeneic CRC xenografts, we observed significantly higher growth of xenografts and infiltrating immune cells in c-Cbl+/− compared to c-Cbl+/+ mice. Tumor-associated CD8+ T-lymphocytes and macrophages of c-Cbl+/− mice showed 2–3-fold higher levels of PD-1. Functionally, macrophages from c-Cbl+/− mice showed a 4–5-fold reduction in tumor phagocytosis, which was restored with an anti-PD-1 neutralizing antibody suggesting regulation of PD-1 by c-Cbl. Further mechanistic probing revealed that C-terminus of c-Cbl interacted with the cytoplasmic tail of PD-1. c-Cbl destabilized PD-1 through ubiquitination- proteasomal degradation depending on c-Cbl’s RING finger function. This data demonstrates c-Cbl as an E3 ligase of PD-1 and a regulator of tumor microenvironment, both of which were unrecognized components of its tumor suppressive activity. Advancing immune checkpoint and c-Cbl biology, our study prompts for probing of PD-1 regulation by c-Cbl in conditions driven by immune checkpoint abnormalities such as cancers and autoimmune diseases.

ROS-responsive nanomedicine: Towards targeting the breast tumor microenvironment

2020 ◽  
Vol 28 ◽  
Author(s):  
RamaRao Malla ◽  
Mohammad Amjad Kamal
Keyword(s):  
Reactive Oxygen Species ◽  
Gene Therapy ◽  
Drug Resistance ◽  
Molecular Imaging ◽  
Tumor Microenvironment ◽  
Immune Cells ◽  
Breast Tumor ◽  
Imaging Techniques ◽  
Oxygen Species ◽  
Massive Accumulation

: The breast tumor microenvironment (TME) promotes drug resistance through an elaborated interaction of TME components mediated by reactive oxygen species (ROS). Despite a massive accumulation of data concerning the targeting the ROS, but little is known about the ROS-responsive nanomedicine for targeting breast TME. This review submits the ROS landscape in breast TME, including ROS biology, ROS mediated carcinogenesis, reprogramming of stromal and immune cells of TME. We also discussed ROS-based precision strategies for imaging TME, including molecular imaging techniques with advanced probes, multiplexed methods, and multi-omic profiling strategies. ROS-responsive nanomedicine also describes various therapies, such as chemo-dynamic, photodynamic, photothermal, sono-dynamic, immune, and gene therapy for BC. We expound ROS-responsive primary delivery systems for chemotherapeutics, phytochemicals, and immunotherapeutics. This review also presents recent updates on nano-theranostics for simultaneous diagnosis and treatment of BCs. We assume that review on this advancing field will be beneficial to the development of ROS-based nanotheranostics for BC.

Metabolism in the Tumor Microenvironment: What is Known about Stromal and Immune Cells?

2018 ◽  
Vol 4 (1) ◽  
Author(s):  
Mª Carmen Ocana ◽  
Beatriz Martinez-Poveda ◽  
Ana R. Quesada ◽  
Miguel Angel Medina
Keyword(s):  
Tumor Microenvironment ◽  
Immune Cells
Sign in / Sign up

Export Citation Format

Share Document