scholarly journals αvβ3-integrin regulates PD-L1 expression and is involved in cancer immune evasion

2019 ◽  
Vol 116 (40) ◽  
pp. 20141-20150 ◽  
Author(s):  
Andrea Vannini ◽  
Valerio Leoni ◽  
Catia Barboni ◽  
Mara Sanapo ◽  
Anna Zaghini ◽  
...  
Keyword(s):  
Immune Evasion ◽  
Αvβ3 Integrin ◽  
Primary Tumors ◽  
Effective Strategies ◽  
Immune Mediated ◽  
Programmed Death ◽  
Programmed Death 1 ◽  
Β3 Integrin ◽  
Immunotherapy Target ◽  
Immunosuppressive Microenvironment

Tumors utilize a number of effective strategies, including the programmed death 1/PD ligand 1 (PD-1/PD-L1) axis, to evade immune-mediated control of their growth. PD-L1 expression is mainly induced by IFN receptor signaling or constitutively induced. Integrins are an abundantly expressed class of proteins which play multiple deleterious roles in cancer and exert proangiogenic and prosurvival activities. We asked whether αvβ3-integrin positively regulates PD-L1 expression and the anticancer immune response. We report that αvβ3-integrin regulated constitutive and IFN-induced PD-L1 expression in human and murine cancerous and noncancerous cells. αvβ3-integrin targeted STAT1 through its signaling C tail. The implantation of β3-integrin–depleted tumor cells led to a dramatic decrease in the growth of primary tumors, which exhibited reduced PD-L1 expression and became immunologically hot, with increased IFNγ content and CD8+ cell infiltration. In addition, the implantation of β3-integrin–depleted tumors elicited an abscopal immunotherapeutic effect measured as protection from the challenge tumor and durable splenocyte and serum reactivity to B16 cell antigens. These modifications to the immunosuppressive microenvironment primed cells for checkpoint (CP) blockade. When combined with anti–PD-1, β3-integrin depletion led to durable therapy and elicited an abscopal immunotherapeutic effect. We conclude that in addition to its previously known roles, αvβ3-integrin serves as a critical component of the cancer immune evasion strategy and can be an effective immunotherapy target.

scholarly journals A case report of psoriasis flare following immunotherapy: Report of an important entity and literature review

2020 ◽  
Vol 8 ◽  
pp. 2050313X1989770 ◽  
Author(s):  
Anastasia Politi ◽  
Dimas Angelos ◽  
Davide Mauri ◽  
George Zarkavelis ◽  
George Pentheroudakis
Keyword(s):  
Adverse Events ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitors ◽  
Skin Lesions ◽  
Inflammatory Disorder ◽  
Immune Mediated ◽  
Programmed Death ◽  
History Of ◽  
Programmed Death 1 ◽  
Cessation Of Treatment

Immune checkpoint inhibitors, such as anti-cytotoxic T-lymphocyte–associated antigen-4 and anti-programmed death-1, are a type of cancer immunotherapy approved for late-stage malignancy treatment. However, such therapies often induce immune-related adverse events. During anti-programmed death-1 blockade therapy, the most commonly reported adverse effects are skin toxicities, such as psoriasis—a chronic immune-mediated inflammatory disorder affecting the skin. We present the clinical characteristics of flared psoriasis in one patient under anti-programmed death-1 therapy who was diagnosed with T2N2M0/IIIB squamous lung carcinoma with a history of psoriasis for the past 5 years, exacerbated after the first cycle of nivolumab. After the third cycle, the extensive skin plaques necessitated treatment cessation. Following the discontinuation of anti-programmed death-1 treatment, skin lesions were treated locally. Possibly, anti-programmed death-1 immunotherapy can trigger immune-mediated diseases, such as psoriasis. Physicians should be alert to immune-related adverse events. Continuation or permanent cessation of treatment depends on the severity and reversibility of immune-related adverse events.

scholarly journals Evolving Concepts: Immunity in Oncology from Targets to Treatments

2015 ◽  
Vol 2015 ◽  
pp. 1-15 ◽  
Author(s):  
Hina Khan ◽  
Rasim Gucalp ◽  
Iuliana Shapira
Keyword(s):  
Cancer Cells ◽  
Immune Checkpoint ◽  
Suppressive Effect ◽  
Anticancer Activities ◽  
Immune Balance ◽  
Immune Mediated ◽  
Programmed Death ◽  
Programmed Death 1 ◽  
Immune Ability ◽  
Immune Checkpoint Proteins

Cancer is associated with global immune suppression of the host. Malignancy-induced immune suppressive effect can be circumvented by blocking the immune checkpoint and tip the immune balance in favor of immune stimulation and unleash cytotoxic effects on cancer cells. Human antibodies directed against immune checkpoint proteins: cytotoxic T lymphocytes antigen-4 (CTLA-4) and programmed death-1 (PD-1), programmed death-ligand 1 (PD-L1), have shown therapeutic efficacy in advanced melanoma and non-small-cell lung cancer and other malignancies. Immune check point blockade antibodies lead to diminished tolerance to self and enhanced immune ability to recognize and eliminate cancer cells. As a class these agents have immune-related adverse events due to decreased ability of effector immune cells to discriminate between self and non-self. Seventy percent of patients participating in clinical trials have experienced anticancer activities and varying degrees of immune mediated dose-limiting side effects.

scholarly journals T cell co-stimulatory receptor CD28 is a primary target for PD-1–mediated inhibition

2016 ◽  
Author(s):  
Enfu Hui ◽  
Jeanne Cheung ◽  
Jing Zhu ◽  
Xiaolei Su ◽  
Marcus J. Taylor ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cell Function ◽  
Cell Receptor ◽  
Costimulatory Receptor ◽  
T Cell Function ◽  
Programmed Death ◽  
Programmed Death 1 ◽  
Immunotherapy Target

AbstractProgrammed death-1 (PD-1) is a co-inhibitory receptor that suppresses T cell activation and is an important cancer immunotherapy target. Upon activation by its ligand PD-L1, PD-1 is thought to suppress signaling through the T cell receptor (TCR). Here, by titrating the strength of PD-1 signaling in both biochemical reconstitution systems and in T cells, we demonstrate that the coreceptor CD28 is strongly preferred over the TCR as a target for dephosphorylation by PD-1- recruited Shp2 phosphatase. We also show that PD-1 colocalizes with the costimulatory receptor CD28 in plasma membrane microclusters but partially segregates from the TCR. These results reveal that PD-1 suppresses T cell function primarily by inactivating CD28 signaling, suggesting that costimulatory pathways may play unexpected roles in regulating effector T cell function and therapeutic responses to anti-PD-L1/PD-1.

PD-1–PD-1 ligand interaction contributes to immunosuppressive microenvironment of Hodgkin lymphoma

Blood ◽  
2008 ◽  
Vol 111 (6) ◽  
pp. 3220-3224 ◽  
Author(s):  
Ryo Yamamoto ◽  
Momoko Nishikori ◽  
Toshio Kitawaki ◽  
Tomomi Sakai ◽  
Masakatsu Hishizawa ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Hodgkin Lymphoma ◽  
Signaling Pathway ◽  
Ligand Interaction ◽  
Tumor Immune Evasion ◽  
T Cell Lymphomas ◽  
Programmed Death ◽  
Programmed Death 1 ◽  
Immunosuppressive Microenvironment

Abstract Programmed death-1 (PD-1)–PD-1 ligand (PD-L) signaling system is involved in the functional impairment of T cells such as in chronic viral infection or tumor immune evasion. We examined PD-L expression in lymphoid cell lines and found that they were up-regulated on Hodgkin lymphoma (HL) and several T-cell lymphomas but not on B-cell lymphomas. PD-L expression was also demonstrated in primary Hodgkin/Reed-Sternberg (H/RS) cells. On the other hand, PD-1 was elevated markedly in tumor-infiltrating T cells of HL, and was high in the peripheral T cells of HL patients as well. Blockade of the PD-1 signaling pathway inhibited SHP-2 phosphorylation and restored the IFN-γ–producing function of HL-infiltrating T cells. According to these results, deficient cellular immunity observed in HL patients can be explained by “T-cell exhaustion,” which is led by the activation of PD-1–PD-L signaling pathway. Our finding provides a potentially effective immunologic strategy for the treatment of HL.

scholarly journals The role of Programmed Death-Ligand 1 expression in nasopharyngeal carcinoma

2021 ◽  
Vol 50 (2) ◽  
pp. 174
Author(s):  
Nadya Dwi Karsa
Keyword(s):  
Nasopharyngeal Carcinoma ◽  
Cancer Cells ◽  
Growth And Development ◽  
Cell Mediated Immunity ◽  
Significant Prognostic Factor ◽  
Programmed Death Ligand 1 ◽  
Programmed Death ◽  
Programmed Death 1 ◽  
Immunotherapy Target

ABSTRACTBackground: Nasopharyngeal carcinoma (NPC) is a malignant tumor that arises from the epithelial cell that cover surface of the nasopharynx, which has the highest incidence of all types of head and neck cancer. Cell-mediated immunity plays an important role in the growth and development of NPC. The expressions of Programmed Death-Ligand 1 (PD-L1) of NPC is still being debated and researched. Objective: To find out and understand the role of PD-L1 expression in NPC. Literature review: PD-L1 is a ligand from Programmed Death-1 (PD-1) receptors that could be expressed by cancer cells. When the PD-1/PD-L1 pathway is active, it promotes survival of cancer cells via anti apoptotic signals and inhibits the activation of signaling pathways, which are critical for survival of T cells. Conclusion: Various studies had found an increase of the PD-L1 expression in NPC cancer cells. PD-L1 is also a potentially important tumor immunotherapy target and can be a significant prognostic factor in NPC. ABSTRAKLatar belakang: Karsinoma nasofaring (KNF) merupakan suatu tumor ganas epitelial nasofaring yang mempunyai insiden tertinggi di antara kanker kepala dan leher. Imunitas selular mempunyai peran penting terhadap pertumbuhan dan perkembangan KNF. Ekspresi Programmed Death-Ligand  1 (PD-L1) pada KNF masih diperdebatkan dan diteliti. Tujuan: Mengetahui dan memahami peran PD-L1 terhadap kejadian KNF. Tinjauan Pustaka: PD-L1 merupakan ligan dari reseptor Programmed Death-1 (PD-1) yang dapat diekpresikan oleh sel kanker. Jalur PD-1 / PD-L1 yang teraktivasi akan melindungi sel kanker melalui sinyal anti apoptosis dan menghambat aktivasi jalur-jalur pengiriman sinyal lain yang sangat penting untuk kelangsungan hidup sel T. Kesimpulan: Berbagai penelitian menemukan adanya peningkatan ekspresi PD-L1 pada sel kanker KNF. PD-L1 menjadi suatu target imunoterapi yang sangat penting dalam meningkatkan respon imun terhadap sel kanker dan dapat dijadikan suatu faktor prognosis pada KNF.

Mutually exclusive expression of CD73 and PDL1 in tumors from patients (pt) with NSCLC, gastroesophageal (GE) and urothelial bladder carcinoma (UBC).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 3079-3079 ◽  
Author(s):  
Philip Martin ◽  
Andreas Spitzmueller ◽  
Song Wu ◽  
Moritz Widmaier ◽  
RENE KORN ◽  
...  
Keyword(s):  
Immune Evasion ◽  
Meta Analysis ◽  
High Expression ◽  
Cd8 Cells ◽  
Urothelial Bladder Carcinoma ◽  
Programmed Death ◽  
Urothelial Bladder ◽  
Programmed Death 1 ◽  
Cd73 Expression ◽  
Anti Tumor Activity

3079 Background: Tumors use multiple means of immune evasion, notably the programmed death-1 (PD1)/PDL1 pathway. Anti-PD1/PDL1 therapy induces anti-tumor activity and has improved pt outcomes. Activation of the immunosuppressive CD39/CD73/adenosine pathway might play a role in pts who do not benefit from anti-PD1/PDL1 therapies. We evaluated expression of CD73 and PDL1 and explored the association between CD73 and intraepithelial (IE) CD8+ cells (TILs) to begin to understand their potential interplay in cancer. Methods: Immunohistochemistry for PDL1, CD73 and CD8 was conducted on tumors of non-squamous NSCLC (NSq) (n=42), GE (n=50), and UBC (n=50). PDL1 and CD73 were scored by image analysis with Definiens software. IE CD8+ TILs were scored semi-quantitatively by a pathologist (0-2 = low; 3-4 = high). Using the top tertile of PDL1 and CD73 for high expression levels, a Fisher’s meta-analysis was calculated across the three indications. Results: Across all tumors, 25% (35/142) were PDL1 high (+), but CD73 low (-) and another 25% (35/142) were CD73+ but PDL1- (p=0.06, see table). This trend for mutually exclusive high expression of PDL1/CD73 was strongest in GE (p<0.01). In the PDL1+ group 76% (35/46) had high IE CD8+ TILs whereas in the CD73+ group only 35% (16/46) had high TILs (p<0.0001 using a proportions test). In the PDL1+/CD73- pt subset 77% (27/35) were CD8+ high vs only 23% (8/35) in the PDL1-/CD73+ subset. Conclusions: The identification of distinct pt subsets based on high PDL1 and/or CD73 expression suggests that tumors have multiple mechanisms of immune evasion. Increased IE CD8+ TILs were associated with PDL1 expression. The finding that PDL1-/ CD73+ tumors have lower IE CD8+ TILs compared to PDL1+/CD73- tumors suggests a role for CD73 in excluding IE TILs. Larger sample sets are needed to confirm these findings and to further explore any relationship with the tumor microenvironment. Our data suggests potential approaches to identify subsets of pts likely to benefit from immunotherapy targeting PDL1 and CD73. [Table: see text]

scholarly journals Autoimmune rhabdomyolysis and a multiorgan display of PD-1 inhibitor induced immune related adverse events during treatment of metastatic melanoma

2019 ◽  
Vol 8 (1) ◽  
Author(s):  
Hoda Z. Pourhassan ◽  
David Tryon ◽  
Brett Schaeffer ◽  
Hamid Mirshahidi ◽  
John Wong
Keyword(s):  
Adverse Events ◽  
Healthcare Providers ◽  
Poor Clinical Outcome ◽  
Case Presentation ◽  
Immune Mediated ◽  
Programmed Death ◽  
Ligand Interactions ◽  
Programmed Death 1 ◽  
Cancer Types ◽  
Nodular Recurrence

Abstract Background Programmed death-1 (PD-1) inhibitors are among the immunotherapies that have revolutionized our approach to treating several cancers. These novel agents act by blocking PD-1 receptor/PD-1 ligand interactions that would otherwise allow tumor cells to evade host immune destruction by inhibiting response of cytotoxic T-lymphocytes. They are overall well tolerated, though they have been associated with a constellation of immune mediated adverse events (irAEs). Case presentation We present a case of rare nivolumab mediated adverse events in a patient with nodular recurrence of melanoma. The patient presented with rhabdomyolysis and shortly thereafter developed a constellation of immune-mediated organ derangements. This case further demonstrates the utility and effectiveness of steroid therapy in the setting of irAEs despite our patient’s eventual poor clinical outcome. While PD-1 inhibitors have revolutionized the treatment of several cancers, they require vigilance by the clinician for early detection and treatment of uncommon but potentially fatal irAEs. Conclusions PD-1 inhibitors are now widely used in a multitude of cancer types including melanoma, advanced non-small cell lung cancer, metastatic renal cell carcinoma, and Hodgkin lymphoma amongst others. While these agents are often well tolerated, they are associated with a unique profile of immune-related toxicities that can cause significant morbidity and mortality. Education of both patients and healthcare providers is essential for diagnosis and treatment of these adverse events early in their course. This case highlights the uncommon but potentially serious PD-1-associated toxicity of myopathy and rhabdomyolysis along with other organ involvement and is directly applicable to use of these agents in patients with advanced cancers.

scholarly journals PD-L1 Expression in Mastocytosis

2019 ◽  
Vol 20 (9) ◽  
pp. 2362 ◽  
Author(s):  
Margaret Williams ◽  
Diane S. Lidke ◽  
Karin Hartmann ◽  
Tracy I. George
Keyword(s):  
Immune Evasion ◽  
Immune Cells ◽  
Targeted Therapies ◽  
Immune Regulation ◽  
Clinical Importance ◽  
Predictive Marker ◽  
Hematologic Neoplasms ◽  
Programmed Death ◽  
Programmed Death 1

Programmed death 1 (PD-1), when activated by its ligands PD-L1 and PD-L2, suppresses active immune cells in normal immune regulation to limit autoimmunity and, in tumors, as a mechanism of immune evasion. PD-L1 expression has been described as both a prognostic and predictive marker in many solid and hematologic neoplasms, as targeted therapies against the PD-1/PD-L1 interaction have gained clinical importance. PD-L1 expression has been assessed in a few studies on mastocytosis. We review this literature and the need for further investigation of the tumor-immune interaction in mastocytosis.

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