EXTH-08. STAT3 AT THE CROSSROADS OF INNATE IMMUNE ACTIVATION IN GLIOBLASTOMA

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi164-vi165
Author(s):  
Christina von Roemeling ◽  
Lan Hoang-Minh ◽  
Bently Doonan ◽  
Chenglong Li ◽  
Duane Mitchell
Keyword(s):  
Immune Suppression ◽  
Immune Cells ◽  
Immune Checkpoint ◽  
Myeloid Cells ◽  
Suppressor Cells ◽  
Immune Checkpoint Blockade ◽  
Innate Immune ◽  
Checkpoint Blockade ◽  
Tumor Bearing ◽  
Stat3 Inhibition

Abstract BACKGROUND Innate immune cells comprise the majority of the immune microenvironment in glioblastoma (GBM) tumors where they are chiefly thought to foster a hospitable environment for cancer cells by regulating immune suppression and driving resistance to immunotherapy. Of these, myeloid-derived suppressor cells (MDSCs) are regarded as one of the most potent contributors to immune suppression in GBM and thus have become a focus of targeted therapy. Signal transducer and activator of transcription 3 (STAT3) is a key phenotypic regulator of MDSCs. Therefore, we sought to examine if targeted STAT3 inhibition may augment the immunogenicity of these tumors. HYPOTHESIS: Targeted STAT3 inhibition reduces GBM tumor infiltration by MDSCs. METHODS Using syngeneic murine models of GBM, we performed pharmacological inhibition analyses using a specific small molecule inhibitor of STAT3, LLL12B. Circulating numbers of immune cells were assessed in tumor bearing animals with or without concomitant focal radiation. Treated tumors were examined for immune infiltrates, and additional phenotyping analyses were performed. Therapeutic responses to LLL12B alone and in combination with immune checkpoint blockade were evaluated. RESULTS STAT3 is activated in the bone marrow of tumor-bearing animals, preferentially by Gr-1 positive granulocytic myeloid cells. Increased circulating numbers of these cells were also detected. These observations were markedly enhanced in tumor-bearing animals following cranial irradiation. Therapeutic inhibition with LLL12B could mitigate these effects, indicating a dependency on STAT3. Within the tumor compartment, granulocytic myeloid cells that successfully infiltrated following treatment demonstrated a pro-inflammatory phenotype denoted by interferon-gamma expression. Improved survival was also observed following combination treatment with LLL12B and radiation or immune checkpoint blockade. CONCLUSIONS These findings advocate a critically important role for STAT3 in regulating granulocytic myeloid cell mobilization and trafficking to GBM tumors. It further illustrates the plasticity of these cells within these tumors, which may be useful in designing successful immunotherapeutic strategies.

scholarly journals Targeting Myeloid-Derived Suppressor Cells to Enhance the Antitumor Efficacy of Immune Checkpoint Blockade Therapy

2021 ◽  
Vol 12 ◽  
Author(s):  
Xueyan Li ◽  
Jiahui Zhong ◽  
Xue Deng ◽  
Xuan Guo ◽  
Yantong Lu ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Myeloid Cells ◽  
Suppressor Cells ◽  
Therapy Resistance ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Antitumor Efficacy ◽  
Myeloid Derived Suppressor Cells ◽  
Immature Myeloid Cells ◽  
Different Levels

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells that are activated under pathological conditions, such as cancer, or mature myeloid cells that are converted immune-suppressive cells via tumor-derived exosomes, and potently support the tumor processes at different levels. Currently, multiple studies have demonstrated that MDSCs induce immune checkpoint blockade (ICB) therapy resistance through their contribution to the immunosuppressive network in the tumor microenvironment. In addition, non-immunosuppressive mechanisms of MDSCs such as promotion of angiogenesis and induction of cancer stem cells also exert a powerful role in tumor progression. Thus, MDSCs are potential therapeutic targets to enhance the antitumor efficacy of ICB therapy in cases of multiple cancers. This review focuses on the tumor-promoting mechanism of MDSCs and provides an overview of current strategies that target MDSCs with the objective of enhancing the antitumor efficacy of ICB therapy.

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.

scholarly journals Targeting Metabolism to Control Immune Responses in Cancer and Improve Checkpoint Blockade Immunotherapy

Cancers ◽  
2021 ◽  
Vol 13 (23) ◽  
pp. 5912
Author(s):  
Angèle Luby ◽  
Marie-Clotilde Alves-Guerra
Keyword(s):  
Cancer Immunotherapy ◽  
Immune Cells ◽  
Immune Checkpoint ◽  
Metabolic Pathways ◽  
Cancer Metabolism ◽  
Metabolic Stress ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
New Therapeutic Approaches ◽  
Immunosuppressive Tumor Microenvironment

Over the past decade, advances in cancer immunotherapy through PD1–PDL1 and CTLA4 immune checkpoint blockade have revolutionized the management of cancer treatment. However, these treatments are inefficient for many cancers, and unfortunately, few patients respond to these treatments. Indeed, altered metabolic pathways in the tumor play a pivotal role in tumor growth and immune response. Thus, the immunosuppressive tumor microenvironment (TME) reprograms the behavior of immune cells by altering their cellular machinery and nutrient availability to limit antitumor functions. Today, thanks to a better understanding of cancer metabolism, immunometabolism and immune checkpoint evasion, the development of new therapeutic approaches targeting the energy metabolism of cancer or immune cells greatly improve the efficacy of immunotherapy in different cancer models. Herein, we highlight the changes in metabolic pathways that regulate the differentiation of pro- and antitumor immune cells and how TME-induced metabolic stress impedes their antitumor activity. Finally, we propose some drug strategies to target these pathways in the context of cancer immunotherapy.

scholarly journals Opposing Functions of Interferon Coordinate Adaptive and Innate Immune Responses to Cancer Immune Checkpoint Blockade

Cell ◽  
2019 ◽  
Vol 178 (4) ◽  
pp. 933-948.e14 ◽  
Author(s):  
Joseph L. Benci ◽  
Lexus R. Johnson ◽  
Ruth Choa ◽  
Yuanming Xu ◽  
Jingya Qiu ◽  
...  
Keyword(s):  
Immune Responses ◽  
Immune Checkpoint ◽  
Immune Checkpoint Blockade ◽  
Innate Immune ◽  
Checkpoint Blockade ◽  
Innate Immune Responses

scholarly journals Antitumor Peptide-Based Vaccine in the Limelight

Vaccines ◽  
2022 ◽  
Vol 10 (1) ◽  
pp. 70
Author(s):  
Takumi Kumai ◽  
Hidekiyo Yamaki ◽  
Michihisa Kono ◽  
Ryusuke Hayashi ◽  
Risa Wakisaka ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Immune Cells ◽  
Immune Checkpoint ◽  
Tumor Antigens ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Recent Experimental Data ◽  
Proof Of Concept ◽  
Cell Responses ◽  
Tumor Reduction

The success of the immune checkpoint blockade has provided a proof of concept that immune cells are capable of attacking tumors in the clinic. However, clinical benefit is only observed in less than 20% of the patients due to the non-specific activation of immune cells by the immune checkpoint blockade. Developing tumor-specific immune responses is a challenging task that can be achieved by targeting tumor antigens to generate tumor-specific T-cell responses. The recent advancements in peptide-based immunotherapy have encouraged clinicians and patients who are struggling with cancer that is otherwise non-treatable with current therapeutics. By selecting appropriate epitopes from tumor antigens with suitable adjuvants, peptides can elicit robust antitumor responses in both mice and humans. Although recent experimental data and clinical trials suggest the potency of tumor reduction by peptide-based vaccines, earlier clinical trials based on the inadequate hypothesis have misled that peptide vaccines are not efficient in eliminating tumor cells. In this review, we highlighted the recent evidence that supports the rationale of peptide-based antitumor vaccines. We also discussed the strategies to select the optimal epitope for vaccines and the mechanism of how adjuvants increase the efficacy of this promising approach to treat cancer.

scholarly journals CCL17/CCL22 Predict the Survival and Response to Immune Checkpoint Blockade Therapy of Patients with HNSCC

2021 ◽  
Author(s):  
Wenkai Zhou ◽  
Xu Zhang ◽  
Yin Long ◽  
Xiaohu Lin ◽  
Yu Zhang ◽  
...  
Keyword(s):  
T Cells ◽  
Immune Cells ◽  
Immune Checkpoint ◽  
Predictive Biomarker ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
High Expression ◽  
New Strategy ◽  
And Function ◽  
Collaborative Activities

Abstract Background: Head and neck squamous cell carcinoma (HNSCC) was considered as an immunosuppressive disease. Cross-talk between cancer cells and immune cells is modulated in part by chemokines CC ligands (CCL). However, the prognostic value and function of CCL in HNSCC have not been clarified. Methods: To identify the key members of CCL family, CCL17 and CCL22 were selected through co-expression analysis. We further evaluated the correlation between the expression of CCL17/CCL22 and cancer immune infiltration through TIMER and scRNA-seq data. TIDE database was used to evaluate whether these molecules can be used as targets for immunotherapy.Results: The results indicated high expression of CCL17 and CCL22 were associated with a better prognosis. CCL17/CCL22 might regulate the T cells activation and were positively correlated with the CD4+ T cells infiltration levels. CCL17/CCL22 can also act as a predictive biomarker for the response to immune checkpoint blockade in HNSCC patients.Conclusions: High expression of CCL17/CCL22 may predict a better response of immune checkpoint blockade therapy in HNSCC. These findings may elucidate the roles played by CCL17/CCL22 in HNSCC progression and identify a new strategy in promoting collaborative activities in the context of immunotherapy.

scholarly journals Collagenase-Expressing Salmonella Targets Major Collagens in Pancreatic Cancer and Improves Immune Checkpoint Blockade

2021 ◽  
Author(s):  
Nancy Danielle Ebelt ◽  
Vic Zamloot ◽  
Edith Zuniga ◽  
Kevin B Passi ◽  
Lukas J. Sobocinski ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Extracellular Matrix ◽  
Immune Checkpoint ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Ductal Adenocarcinoma ◽  
Therapeutic Resistance ◽  
Collagen Deposition ◽  
Tumor Bearing ◽  
Bacterial Collagenase

Therapeutic resistance in pancreatic ductal adenocarcinoma (PDAC) can be attributed, in part, to a dense extracellular matrix containing excessive collagen deposition. Here, we describe a novel Salmonella typhimurium (ST) vector expressing the bacterial collagenase Streptomyces omiyaensis trypsin (SOT), a serine protease known to hydrolyze collagens I and IV, which are predominantly found in PDAC. Utilizing aggressive models of PDAC, we show that ST-SOT selectively degrades intratumoral collagen leading to enhancement of immune checkpoint blockade (ICB) therapy in tumor-bearing mice. Ultimately, we found that ST-SOT treatment significantly modifies the intratumoral immune landscape to generate a microenvironment more conducive to ICB.

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