scholarly journals Transforming of the Tumor Microenvironment: Implications for TGF-βInhibition in the Context of Immune-Checkpoint Therapy

2018 ◽  
Vol 2018 ◽  
pp. 1-9 ◽  
Author(s):  
Stefanie Löffek
Keyword(s):  
Tumor Microenvironment ◽  
Transforming Growth Factor Beta ◽  
Immune Checkpoint ◽  
Transforming Growth Factor ◽  
Treatment Strategies ◽  
Therapy Response ◽  
Initial Therapy ◽  
Therapeutic Benefit ◽  
Immune Checkpoint Blockade ◽  
Oncogenic Signaling

Significant breakthroughs have been achieved in the fields of oncogenic signaling inhibition and particularly immune-checkpoint blockade has triggered substantial enthusiasm during the last decade. Antibody-mediated blockade of negative immune-checkpoint molecules (e.g., PD-1/PD-L1, CTLA-4) has been shown to achieve profound responses in several of solid cancers. Unfortunately, these responses only occur in a subset of patients or, after initial therapy response, these tumors eventually relapse. Thus, elucidating the determinants of intrinsic or therapy-induced resistance is the key to improve outcomes and developing new treatment strategies. Several cytokines and growth factors are involved in the tight regulation of either antitumor immunity or immunosuppressive tumor-promoting inflammation within the tumor microenvironment (TME), of which transforming growth factor beta (TGF-β) is of particular importance. This review will therefore summarize the recent progress that has been made in the understanding of how TGF-βblockade may have the capacity to enhance efficacy of immune-checkpoint therapy which presents a rational strategy to sustain the antitumor inflammatory response to improve response rates in tumor patients. Finally, I will conclude with a comprehensive summary of clinical trials in which TGF-βblockade revealed therapeutic benefit for patients by counteracting tumor relapses.

scholarly journals EXTH-11. TREATMENT WITH DELTA-24-RGDOX OF SUBCUTANEOUS TUMORS RESULTS IN ABSCOPAL EFFECT ERADICATING INTRACRANIAL MELANOMAS

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi84-vi84
Author(s):  
Hong Jiang ◽  
Dong Ho Shin ◽  
Teresa Nguyen ◽  
Marta M Alonso ◽  
Frederick Lang ◽  
...  
Keyword(s):  
T Cells ◽  
Immune Checkpoint ◽  
Treatment Strategies ◽  
Therapeutic Benefit ◽  
Intratumoral Injection ◽  
Immune Checkpoint Blockade ◽  
Oncolytic Adenovirus ◽  
Checkpoint Blockade ◽  
Target Antigen ◽  
Brain Hemispheres

Abstract Immune checkpoint blockade has revolutionized cancer therapy; however the therapeutic benefit is limited to only a subset of patients with immunogenic (“hot”) tumors and is compromised by immune-related adverse events. We have reported the efficacy of oncolytic adenovirus Delta-24-RGDOX (DNX-2440) in syngeneic glioma mouse models. We hypothesized that localized treatment with the virus is effective against disseminated melanomas, including intracranial melanomas. We tested the hypothesis in the subcutaneous (s.c.)/s.c. and s.c./intracranial (i.c.) melanoma models derived from luciferase-expressing B16-Red-FLuc cells in C57BL/6 mice. First, through monitoring tumor growth with bioluminescence imaging, we found that, in both s.c./s.c. and s.c./i.c. models, three injections of Delta-24-RGDOX significantly inhibited the growth of both the virus-injected s.c. tumor and untreated distant s.c. or i.c. tumor, thereby prolonging survival. Next, through cell profiling with flow cytometry, we observed that the virus increased the presence of T cells and effector T cell frequency in the virus-injected tumor and mediated the same changes in T cells from peripheral blood, tumor-draining lymph nodes (TDLNs), spleens, and brain hemispheres with untreated tumor. Moreover, Delta-24-RGDOX decreased the frequency of exhausted T cells and regulatory T cells in the virus-injected and untreated i.c. tumors. Consequently, the virus promoted recruitment and/or in situ expansion of antigen-specific T cells in tumors expressing the target antigen. Therefore, we concluded that local intratumoral injection of Delta-24-RGDOX resulted in systemic immune activity against the disseminated tumors. Furthermore, we speculate that given the immunogenicity, cancer-selectivity and intratumoral administration of the virus, Delta-24-RGDOX is expected to have an improved safety profile when compared to immune checkpoint blockade treatment strategies. This is the first report demonstrating that local administration of oncolytic adenovirus results in eradication of intracranial tumors, suggesting Delta-24-RGDOX could be used to manage brain metastases of melanoma.

scholarly journals A TLR4 agonist improves immune checkpoint blockade treatment by increasing the ratio of effector to regulatory cells within the tumor microenvironment

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
A. Farias ◽  
A. Soto ◽  
F. Puttur ◽  
C. J. Goldin ◽  
S. Sosa ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Growth ◽  
Therapeutic Effect ◽  
Immune Cells ◽  
Immune Checkpoint ◽  
Combined Treatment ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Regulatory Cells ◽  
Ifn Γ

AbstractBrucella lumazine synthase (BLS) is a homodecameric protein that activates dendritic cells via toll like receptor 4, inducing the secretion of pro-inflammatory cytokines and chemokines. We have previously shown that BLS has a therapeutic effect in B16 melanoma-bearing mice only when administered at early stages of tumor growth. In this work, we study the mechanisms underlying the therapeutic effect of BLS, by analyzing the tumor microenvironment. Administration of BLS at early stages of tumor growth induces high levels of serum IFN-γ, as well as an increment of hematopoietic immune cells within the tumor. Moreover, BLS-treatment increases the ratio of effector to regulatory cells. However, all treated mice eventually succumb to the tumors. Therefore, we combined BLS administration with anti-PD-1 treatment. Combined treatment increases the outcome of both monotherapies. In conclusion, we show that the absence of the therapeutic effect at late stages of tumor growth correlates with low levels of serum IFN-γ and lower infiltration of immune cells in the tumor, both of which are essential to delay tumor growth. Furthermore, the combined treatment of BLS and PD-1 blockade shows that BLS could be exploited as an essential immunomodulator in combination therapy with an immune checkpoint blockade to treat skin cancer.

Targeting the tumor microenvironment to overcome immune checkpoint blockade therapy resistance

2020 ◽  
Vol 220 ◽  
pp. 88-96 ◽  
Author(s):  
Yaqi Li ◽  
Jing Liu ◽  
Long Gao ◽  
Yuan Liu ◽  
Fang Meng ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Immune Checkpoint ◽  
Therapy Resistance ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade

scholarly journals Sensitization to immune checkpoint blockade through activation of a STAT1/NK axis in the tumor microenvironment

2019 ◽  
Vol 11 (501) ◽  
pp. eaav7816 ◽  
Author(s):  
Rachael M. Zemek ◽  
Emma De Jong ◽  
Wee Loong Chin ◽  
Iona S. Schuster ◽  
Vanessa S. Fear ◽  
...  
Keyword(s):  
Gene Expression ◽  
Tumor Microenvironment ◽  
Nk Cells ◽  
Immune Checkpoint ◽  
Expression Profiles ◽  
Gene Expression Signature ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Poly I:C ◽  
Mouse Strains

Cancer immunotherapy using antibodies that target immune checkpoints has delivered outstanding results. However, responses only occur in a subset of patients, and it is not fully understood what biological processes determine an effective outcome. This lack of understanding hinders the development of rational combination treatments. We set out to define the pretreatment microenvironment associated with an effective outcome by using the fact that inbred mouse strains bearing monoclonal cancer cell line–derived tumors respond in a dichotomous manner to immune checkpoint blockade (ICB). We compared the cellular composition and gene expression profiles of responsive and nonresponsive tumors from mice before ICB and validated the findings in cohorts of patients with cancer treated with ICB antibodies. We found that responsive tumors were characterized by an inflammatory gene expression signature consistent with up-regulation of signal transducer and activator of transcription 1 (STAT1) and Toll-like receptor 3 (TLR3) signaling and down-regulation of interleukin-10 (IL-10) signaling. In addition, responsive tumors had more infiltrating-activated natural killer (NK) cells, which were necessary for response. Pretreatment of mice with large established tumors using the STAT1-activating cytokine interferon-γ (IFNγ), the TLR3 ligand poly(I:C), and an anti–IL-10 antibody sensitized tumors to ICB by attracting IFNγ-producing NK cells into the tumor, resulting in increased cure rates. Our results identify a pretreatment tumor microenvironment that predicts response to ICB, which can be therapeutically attained. These data suggest a biomarker-driven approach to patient management to establish whether a patient would benefit from treatment with sensitizing therapeutics before ICB.

scholarly journals Impact of the Tumor Microenvironment on Tumor-Infiltrating Lymphocytes: Focus on Breast Cancer

2017 ◽  
Vol 11 ◽  
pp. 117822341773156 ◽  
Author(s):  
Ivan J Cohen ◽  
Ronald Blasberg
Keyword(s):  
Breast Cancer ◽  
Immune Response ◽  
Clinical Trials ◽  
Tumor Microenvironment ◽  
Immune Checkpoint ◽  
Tumor Infiltrating Lymphocytes ◽  
Breast Tumors ◽  
Immune Checkpoint Blockade ◽  
Physical Barriers ◽  
Infiltrating Lymphocytes

Immunotherapy is revolutionizing cancer care across disciplines. The original success of immune checkpoint blockade in melanoma has already been translated to Food and Drug Administration–approved therapies in a number of other cancers, and a large number of clinical trials are underway in many other disease types, including breast cancer. Here, we review the basic requirements for a successful antitumor immune response, with a focus on the metabolic and physical barriers encountered by lymphocytes entering breast tumors. We also review recent clinical trials of immunotherapy in breast cancer and provide a number of interesting questions that will need to be answered for successful breast cancer immunotherapy.

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