scholarly journals Modulation of SRSF2 expression reverses the exhaustion of TILs via the epigenetic regulation of immune checkpoint molecules

2019 ◽  
Vol 77 (17) ◽  
pp. 3441-3452 ◽  
Author(s):  
Ziqiang Wang ◽  
Kun Li ◽  
Wei Chen ◽  
Xiaoxia Wang ◽  
Yikun Huang ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Microenvironment ◽  
Immune Checkpoint ◽  
Tumor Infiltrating Lymphocytes ◽  
Immune Checkpoints ◽  
Gene Promoters ◽  
Immune Checkpoint Molecules ◽  
Elevated Expression ◽  
Infiltrating Lymphocytes ◽  
Checkpoint Genes

AbstractThe elevated expression of immune checkpoints by the tumor microenvironment is associated with poor prognosis in several cancers due to the exhaustion of tumor-infiltrating lymphocytes (TILs), and the effective suppression of the expression of these genes is key to reversing the exhaustion of TILs. Herein, we determined that serine/arginine-rich splicing factor 2 (SRSF2) is a target for blocking the tumor microenvironment-associated immunosuppressive effects. We found that the expression of SRSF2 was increased in exhausted T cells and that SRSF2 was involved in multiple immune checkpoint molecules mediating TILs’ exhaustion. Furthermore, SRSF2 was revealed to regulate the transcription of these immune checkpoint genes by associating with an acyl-transferases P300/CBP complex and altering the H3K27Ac level near these genes, thereafter influencing the recruitment of signal transducer and activator of transcription 3 (STAT3) to these gene promoters. Collectively, our data indicated that SRSF2 functions as a modulator of the anti-tumor response of T cells and may be a therapeutic target for reversing the exhaustion of TILs.

scholarly journals Tumor microenvironment in triple-negative breast cancer: the correlation of tumor-associated macrophages and tumor-infiltrating lymphocytes

2021 ◽  
Author(s):  
H. Kuroda ◽  
T. Jamiyan ◽  
R. Yamaguchi ◽  
A. Kakumoto ◽  
A. Abe ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
Tumor Microenvironment ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Cytotoxic T Cells ◽  
Tumor Infiltrating Lymphocytes ◽  
Tumor Associated Macrophages ◽  
Free Survival ◽  
Infiltrating Lymphocytes

Abstract Purpose Immune cells such as cytotoxic T cells, helper T cells, B cells or tumor-associated macrophages (TAMs) contribute to the anti-tumor response or pro-tumorigenic effect in triple negative breast cancer (TNBC). The interrelation of TAMs, T and B tumor-infiltrating lymphocytes (TILs) in TNBC has not been fully elucidated. Methods We evaluated the association of tumor-associated macrophages, T and B TILs in TNBC. Results TNBCs with a high CD68+, CD163+ TAMs and low CD4+, CD8+, CD20+ TILs had a significantly shorter relapse-free survival (RFS) and overall survival (OS) than those with low CD68+, CD163+ TAMs and high CD4+, CD8+, CD20+ TILs. TNBCs with high CD68+ TAMs/low CD8+ TILs showed a significantly shorter RFS and OS and a significantly poorer prognosis than those with high CD68+ TAMs/high CD8+ TILs, low CD68+ TAMs/high CD8+ TILs, and low CD68+/low CD8+. TNBCs with high CD163+ TAMs/low CD8+, low CD20 + TILs showed a significantly shorter RFS and OS and a significantly poorer prognosis than those with high CD163+ TAMs/high CD8+ TILs and high CD163+ TAMs /high CD20+ TILs. Conclusions Our study suggests that TAMs further create an optimal tumor microenvironment (TME) for growth and invasion of cancer cells when evasion of immunoreactions due to T and B TILs occurs. In TNBCs, all these events combine to affect prognosis. The process of TME is highly complex in TNBCs and for an improved understanding, larger validation studies are necessary to confirm these findings.

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.

Immunocytokines are a promising immunotherapeutic approach against glioblastoma

2020 ◽  
Vol 12 (564) ◽  
pp. eabb2311 ◽  
Author(s):  
Tobias Weiss ◽  
Emanuele Puca ◽  
Manuela Silginer ◽  
Teresa Hemmerle ◽  
Shila Pazahr ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Microenvironment ◽  
Cd8 T Cells ◽  
Tumor Necrosis ◽  
Interleukin 2 ◽  
Blood Perfusion ◽  
Tumor Infiltrating Lymphocytes ◽  
Infiltrating Lymphocytes ◽  
Necrosis Factor ◽  
New Strategies

Glioblastoma is a poorly immunogenic cancer, and the successes with recent immunotherapies in extracranial malignancies have, so far, not been translated to this devastating disease. Therefore, there is an urgent need for new strategies to convert the immunologically cold glioma microenvironment into a hot one to enable effective antitumor immunity. Using the L19 antibody, which is specific to a tumor-associated epitope of extracellular fibronectin, we developed antibody-cytokine fusions—immunocytokines—with interleukin-2 (IL2), IL12, or tumor necrosis factor (TNF). We showed that L19 accumulated in the tumor microenvironment of two orthotopic immunocompetent mouse glioma models. Furthermore, intravenous administration of L19-mIL12 or L19-mTNF cured a proportion of tumor-bearing mice, whereas L19-IL2 did not. This therapeutic activity was abolished in RAG−/− mice or upon depletion of CD4 or CD8 T cells, suggesting adaptive immunity. Mechanistically, both immunocytokines promoted tumor-infiltrating lymphocytes and increased the amounts of proinflammatory cytokines within the tumor microenvironment. In addition, L19-mTNF induced tumor necrosis. Systemic administration of the fully human L19-TNF fusion protein to patients with glioblastoma (NCT03779230) was safe, decreased regional blood perfusion within the tumor, and was associated with increasing tumor necrosis and an increase in tumor-infiltrating CD4 and CD8 T cells. The extensive preclinical characterization and subsequent clinical translation provide a robust basis for future studies with immunocytokines to treat malignant brain tumors.

PD-1:PD-L1(B7-H1) pathway in adaptive resistance: A novel mechanism for tumor immune escape in human papillomavirus-related head and neck cancers.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 5506-5506 ◽  
Author(s):  
Sofia Lyford-Pike ◽  
Shiwen Peng ◽  
Janis M. Taube ◽  
William H. Westra ◽  
Belinda Akpeng ◽  
...  
Keyword(s):  
T Cells ◽  
Human Papillomavirus ◽  
Tumor Microenvironment ◽  
Head And Neck ◽  
Tumor Cells ◽  
Tumor Infiltrating Lymphocytes ◽  
Adaptive Immune ◽  
Functional Assays ◽  
Immune Resistance ◽  
Infiltrating Lymphocytes

5506 Background: Human papillomavirus-associated head and neck squamous cell carcinomas (HPV-HNSCC) are associated with a strong host immune response. Despite ample tumor infiltrating lymphocytes (TILs), the cancer is able to persist and grow. Here, we provide evidence for an adaptive immune resistance mechanism mediated through the PD-1:PD-L1 pathway. Methods: We evaluated the peripheral blood and tumor infiltrating lymphocytes for PD-1 expression using flow cytometry in HPV-HNSCC patients. We evaluted PD-L1 expression within the tumors using immunohistochemistry. We performed functional assays evaluating IFN-gamma secretion of PD-1+ and PD-1(-) CD8+ T cells isolated from the tumor microenvironment of PD-L1+ and PD-L1(-) HPV-related head and neck cancers. Results: We found the majority of CD8+ TILs in HPV-HNSCC express the PD-1 co-inhibitory receptor. We report a striking association between expression of its ligand PD-L1 on tumor cells and tumor associated macrophages, and the presence of TILs. Interestingly, membranous PD-L1 staining on tumor cells and CD68+ antigen presenting cells was geographically localized to the periphery of tumor nests and juxtaposed to fronts of infiltrating T cells. Functional assays demonstrated that PD-1-dependent T cell inhibition required expression of PD-L1 in the tumor microenvironment. Finally, we report localized expression of PD-L1 in the deep crypts of normal tonsils, the site of HPV infection and origin of HPV-HNSCC. Conclusions: Our findings support the role of the PD-1:PD-L1 interaction in creating an immune-privileged site for initial viral infection and subsequently adaptive immune resistance once tumors are established and suggest a rationale for therapeutic blockade of this pathway in patients with HPV-HNSCC.

Effect of NKTR-214 on the number and activity of CD8+ tumor infiltrating lymphocytes in patients with advanced renal cell carcinoma.

2017 ◽  
Vol 35 (6_suppl) ◽  
pp. 454-454 ◽  
Author(s):  
Michael E. Hurwitz ◽  
Adi Diab ◽  
Chantale Bernatchez ◽  
Cara L. Haymaker ◽  
Harriet M. Kluger ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Microenvironment ◽  
Cd8 T Cells ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Tumor Infiltrating Lymphocytes ◽  
Poor Response ◽  
Post Treatment ◽  
Open Label

454 Background: Patients with low baseline CD8+ T-cells within the tumor microenvironment (TILs) have a poor response to immune checkpoint inhibitors. Agents designed to specifically activate and expand CD8+ T cells may improve clinical outcomes in patients with low TILs. NKTR-214 is a CD-122-biased agonist designed to provide sustained signaling through the heterodimeric IL-2 receptor pathway (IL-2Rβɣ) and preferentially activate and expand NK and effector CD8+ T cells over CD4+ T regulatory cells. Methods: A dose escalation, open-label, trial was initiated to assess the safety of NKTR-214 and explore immune changes in the blood and tumor microenvironment in patients with advanced solid tumors. NKTR-214 was administered IV in an outpatient setting with initial dosing at 0.003 mg/kg. Pre and post treatment blood and tumor samples were analyzed for immune phenotyping, gene expression, T cell receptor diversity, and changes in the tumor microenvironment by immunohistochemistry. Results: Among 25 patients dosed, 15 had RCC ([email protected]/kg, [email protected]/kg, and [email protected]/kg). Treatment with NKTR-214 was well tolerated and the MTD was not reached. One patient experienced DLTs (Gr3 syncope and hypotension) at 0.012 mg/kg. There were no immune-related AEs. Of 12 patients evaluable for response, 75% had SD at their first on treatment scan. Of 5 patients, who were immune checkpoint naïve with ≥ 1 prior TKI treatments, 3 experienced tumor shrinkage, 1 with PR per RECIST 1.1 (unconfirmed). Interrogation of the tumor microenvironment revealed many significant immunological changes post treatment, including increase in total and proliferating NK, CD8+, and CD4+ T cells. There was good correlation between increase in activated CD4+ and CD8+ T cells in peripheral blood with an increase in T cell infiltrates within the tumor tissue. Conclusions: NKTR-214 increased immune infiltration in the tumor and anti-tumor activity in patients who previously progressed on TKIs, with a favorable safety profile. The ability to alter the immune environment and increase PD-1 expression on effectors T cells may improve the effectiveness of anti-PD-1 blockade. A trial combining NKTR-214 and nivolumab is enrolling. Clinical trial information: 02869295.

Effect of STING agonist on tumor immune microenvironment of non-inflamed lung cancer and efficacy of immune checkpoint blockade.

2018 ◽  
Vol 36 (5_suppl) ◽  
pp. 178-178
Author(s):  
Hongjae Chon
Keyword(s):  
Lung Cancer ◽  
T Cells ◽  
T Cell ◽  
Tumor Microenvironment ◽  
Tumor Growth ◽  
Lung Carcinoma ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Immune Checkpoints ◽  
Anti Cancer

178 Background: Cancer immunotherapy targeting immune checkpoints are now emerging as a promising therapeutic strategy in various tumors. However, the treatment of T cell non-inflamed tumor which lacks intratumoral T cell infiltrates are still major clinical hurdle. Therefore, drugs that target signaling pathways to increase T cell infiltration in non-inflamed tumor microenvironment (TME) should be investigated. In this study, we aimed to explore the therapeutic potential of STING agonist in murine model of non-small cell lung cancer to overcome immunotherapy resistance. Methods: C57BL/6 mice, which are 6 to 8 weeks of age, were used for the experiment. Mice were injected with Lewis lung carcinoma cells on the right flank. STING agonist (cGAMP) was injected intratumorally. CD8+ and CD31+ cells were detected using immunofluorescence (IF) staining. Gene expressions of tumor microenvironment were analyzed by NanoString RNA sequencing. Flow cytometry (FACS) was performed to detect CD8+, CD4+, Treg and myeloid cell population. Tumor growths were evaluated in combination with anti-PD1 and STING agonist treatment. Results: Local injection of STING agonist effectively delayed tumor growth of LLC. STING agonist increased intratumoral CD8+ T cells and vascular disruption. Expressions of inhibitory checkpoint molecules (PD-1, PD-L1), cytokines (IFN), CD8+ and CD4+ T cells were increased, which showed that anti-cancer immune responses were augmented. Combination treatment of anti-PD-1 antibody and STING agonist synergistically decreased tumor growth. Conclusions: In this study, STING agonist was shown to delay tumor growth and remodel tumor microenvironment in non-inflamed lung carcinoma model. Combination therapy of STING agonist and immune checkpoint inhibitors (ICI) targeting PD-1 synergistically suppressed the growth of lung cancer which is resistant to ICI monotherapy. Collectively, our findings demonstrated that localized STING therapy effectively sensitizes non-inflamed lung cancer to systemic ICI treatment and induces a maximal anti-cancer immune response.

scholarly journals Strong Expression of the Immune Checkpoint Regulators LAG3 and Tim3 in Hodgkin Lymphoma

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2952-2952 ◽  
Author(s):  
Layal el Halabi ◽  
Julien Adam ◽  
Virginie Marty ◽  
Jacques Bosq ◽  
Julien Lazarovici ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Microenvironment ◽  
Board Of Directors ◽  
Hodgkin Lymphoma ◽  
Immune Checkpoint ◽  
Single Case ◽  
Immune Checkpoint Blockade ◽  
Immune Checkpoints ◽  
Advisory Committees ◽  
Secondary Resistance

Abstract Background: Recent results of immune checkpoint blockade trials have provided a proof of concept for immunotherapy in classical Hodgkin lymphoma (cHL) with more than two third of relapsed/refractory patients responding to blockade of the PD1/PDL1 axis. Unfortunately, there is still a proportion of patients who will present primary or secondary resistance to immunotherapy. Besides the PD1/PDL1 axis, several other molecules are critical regulators of the immune response and may be the target of therapeutic intervention. Combined immune checkpoint targeting has shown interesting results in preclinical and clinical trials in several types of tumors. Methods: Patients with initially diagnosed or relapsed cHL for whom formalin fixed paraffin embedded (FFPE) tissue was available at our institution were identified. Fifty-seven cases were selected depending solely on the availability and the quality of the FFPE blocks. Expression of the following immune checkpoints PD1, PDL1, LAG3, TIM3 was assessed using immunohistochemical methods with a threshold of 5% set for positivity. Results: Complete results for 25 cases were available at the time the abstract was written. Hodgkin and Reed Sternberg cells (HRS) were identified morphologically upon microscopic examination. Consistently with data published in the literature, HRS stained positively and intensely for PDL1 in 100% of the cases (25/25). HRS were positive for Tim3 in 36% (9/25) of cases but with more varying intensities. No PD1 or LAG3 expression was found on HRS cells except for a single case where 5% of HRS stained weakly for LAG3. In the tumor microenvironment, PD1 expression was detected in 65% of cases (15/23) and PDL1 in 60% of cases (15/25). Impressively, LAG3 and TIM3 stained positively in 96% (23/24) and 92% (24/25) of cases respectively. Lymphocyte-rosetting was present in 9/25 cases. These CD4+ FoxP3- T cells surrounding HRS were positive for PD1 in 5 cases, for LAG3 in 2 cases and for both PD1 and LAG3 in 2 cases, suggesting they represented exhausted T-cells. Concomitant expression of PD1 and PDL1 in the tumor microenvironment was present in 43% of cases (10/23). Conclusion: LAG3 and TIM3 are nearly universally expressed in the tumor microenvironment of cHL. These findings provide a strong rationale for their blockade alone or in combination in relapsed/refractory patients with cHL. The role of TIM3 expression by HRS remains unclear. Correlation of these findings with clinical data and survival outcome of the patients will be done for the whole sample. Disclosures Ribrag: NanoString: Membership on an entity's Board of Directors or advisory committees; Esai: Membership on an entity's Board of Directors or advisory committees; ArgenX: Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees; Infinity: Membership on an entity's Board of Directors or advisory committees; Pharmamar: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees.

scholarly journals MicroRNA-326 attenuates immune escape and prevents metastasis in lung adenocarcinoma by targeting PD-L1 and B7-H3

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Lijuan Shao ◽  
Qian He ◽  
Jingbo Wang ◽  
Fei He ◽  
Shengcheng Lin ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Lung Adenocarcinoma ◽  
Tumor Progression ◽  
Tumor Cells ◽  
Immune Checkpoint ◽  
Immune Escape ◽  
Immune Checkpoints ◽  
Tumor Cell Migration ◽  
Immune Checkpoint Molecules

AbstractTumor-infiltrating T cells are highly expressive of inhibitory receptor/immune checkpoint molecules that bind to ligand expressed by tumor cells and antigen-presenting cells, and eventually lead to T cell dysfunction. It is a hot topic to restore T cell function by targeting immune checkpoint. In recent years, immunotherapy of blocking immune checkpoint and its receptor, such as PD-L1/PD-1 targeted therapy, has made effective progress, which brings hope for patients with advanced malignant tumor. However, only a few patients benefit from directly targeting these checkpoints or their receptors by small compounds or antibodies. Since the complexity of the regulation of immune checkpoints in tumor cells, further research is needed to identify the novel endogenous regulators of immune checkpoints which can help for developing effective drug target to improve the effect of immunotherapy. Here, we verified that microRNA-326 (miR-326) repressed the gene expression of immune checkpoint molecules PD-L1 and B7-H3 in lung adenocarcinoma (LUAD). We detected that the expression of miR-326 in LUAD tissue was negatively correlated with PD-L1/B7-H3. The repression of PD-L1 and B7-H3 expression through miR-326 overexpression leads to the modification the cytokine profile of CD8+ T cells and decreased migration capability of tumor cells. Meanwhile, the downregulation of miR-326 promoted tumor cell migration. Moreover, blocking PD-L1 and B7-H3 attenuated the tumor-promoting effect induced by miR-326 inhibitor. In tumor-bearing mice, the infiltration of CD8+ T cells was significantly increased and the expression of TNF-α, and IFN-γ was significantly enhanced which contributed to tumor progression after miR-326 overexpression. Collectively, miR-326 restrained tumor progression by downregulating PD-L1 and B7-H3 expression and increasing T cell cytotoxic function in LUAD. Our findings revealed a novel perspective on the complex regulation of immune checkpoint molecules. A new strategy of using miR-326 in tumor immunotherapy is proposed.

scholarly journals The tumor microenvironment as a metabolic barrier to effector T cells and immunotherapy

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Aaron R Lim ◽  
W Kimryn Rathmell ◽  
Jeffrey C Rathmell
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Microenvironment ◽  
Cell Metabolism ◽  
Tumor Infiltrating Lymphocytes ◽  
T Cell Signaling ◽  
Waste Products ◽  
Cancer Cell Metabolism ◽  
And Function ◽  
Infiltrating Lymphocytes

Breakthroughs in anti-tumor immunity have led to unprecedented advances in immunotherapy, yet it is now clear that the tumor microenvironment (TME) restrains immunity. T cells must substantially increase nutrient uptake to mount a proper immune response and failure to obtain sufficient nutrients or engage the appropriate metabolic pathways can alter or prevent effector T cell differentiation and function. The TME, however, can be metabolically hostile due to insufficient vascular exchange and cancer cell metabolism that leads to hypoxia, depletion of nutrients, and accumulation of waste products. Further, inhibitory receptors present in the TME can inhibit T cell metabolism and alter T cell signaling both directly and through release of extracellular vesicles such as exosomes. This review will discuss the metabolic changes that drive T cells into different stages of their development and how the TME imposes barriers to the metabolism and activity of tumor infiltrating lymphocytes.

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