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 B7-H1 is a ubiquitous antiapoptotic receptor on cancer cells

Blood ◽  
2008 ◽  
Vol 111 (7) ◽  
pp. 3635-3643 ◽  
Author(s):  
Takeshi Azuma ◽  
Sheng Yao ◽  
Gefeng Zhu ◽  
Andrew S. Flies ◽  
Sarah J. Flies ◽  
...  
Keyword(s):  
T Cell ◽  
Cancer Cells ◽  
Immune Cells ◽  
Kinase Inhibitor ◽  
Tumoricidal Activity ◽  
Immune Mediated ◽  
Programmed Death ◽  
Induce Resistance ◽  
Programmed Death 1 ◽  
Increased Susceptibility

Abstract B7-H1 is an immunoglobulin-like immune suppressive molecule broadly detectable on the majority of human and rodent cancers, and its functions have been attributed to delivering an inhibitory signal to its counter-receptor programmed death-1 (PD-1) on T cells. Here we report that B7-H1 on cancer cells receives a signal from PD-1 to rapidly induce resistance against T cell–mediated killing because crippling signaling capacity of B7-H1 but not PD-1 ablates this resistance. Importantly, loss of B7-H1 signaling is accompanied by increased susceptibility to immune-mediated tumoricidal activity. In addition to resistance against T-cell destruction, B7-H1+ cancer cells also become refractory to apoptosis induced by Fas ligation or the protein kinase inhibitor Staurosporine. Our study reveals a new mechanism by which cancer cells use a receptor on immune cells as a ligand to induce resistance to therapy.

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 Majority of B2M-Mutant and -Deficient Colorectal Carcinomas Achieve Clinical Benefit From Immune Checkpoint Inhibitor Therapy and Are Microsatellite Instability-High

2019 ◽  
pp. 1-14 ◽  
Author(s):  
Sumit Middha ◽  
Rona Yaeger ◽  
Jinru Shia ◽  
Zsofia K. Stadler ◽  
Sarah King ◽  
...  
Keyword(s):  
Major Histocompatibility Complex ◽  
Major Histocompatibility Complex Class ◽  
Immune Checkpoint ◽  
Clinical Benefit ◽  
Complex Class ◽  
Colorectal Carcinomas ◽  
Wild Type ◽  
Histocompatibility Complex ◽  
Programmed Death ◽  
Programmed Death 1

PURPOSE Microsatellite instability-high (MSI-H) colorectal carcinomas (CRCs) show high rates of response to immune checkpoint inhibitors (IOs). B2M mutations and protein loss have been proposed as causes of resistance to IOs, yet they are enriched in MSI-H CRC. We aimed to characterize B2M-mutant, IO-naive CRC. PATIENTS AND METHODS All CRCs with results for Memorial Sloan Kettering Integrated Mutation Profiling of Actionable Cancer Targets, a next-generation sequencing assay that interrogates > 400 genes for mutations as well as MSI status, were surveyed for B2M mutations. All B2M-mutant CRCs were assessed for expression of B2M, major histocompatibility complex class I, and programmed death-1 ligand (PD-L1) via immunohistochemistry and average CD3+ and CD8+ tumor-infiltrating lymphocyte counts against a control group of MSI-H B2M wild-type CRCs. RESULTS Fifty-nine (3.4%) of 1,751 patients with CRC harbored B2M mutations, with 84% (77 of 92) of the mutations predicted to be truncating. B2M mutations were significantly enriched in MSI-H CRCs, with 44 (24%) of 182 MSI-H CRCs harboring B2M mutations ( P < .001). Thirty-two of 44 B2M-mutant CRCs with available material (73%) had complete loss of B2M expression, whereas all 26 CRCs with wild-type B2M retained expression ( P < .001). B2M mutation status was not associated with major histocompatibility complex class I expression, KRAS or BRAF mutation, tumor-infiltrating lymphocyte level, or PD-L1 expression after adjustment for MSI status. Of 13 patients with B2M-mutant CRC who received programmed death-1 or PD-L1 IOs, 11 (85%) achieved clinical benefit, defined as stable disease or partial response using Response Evaluation Criteria in Solid Tumors criteria. CONCLUSION B2M mutations occur in approximately 24% of MSI-H CRCs and are usually associated with loss of B2M expression. Most patients with B2M-mutant MSI-H CRC with loss of protein expression obtain clinical benefit from IOs.

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 Disparities in the Use of Programmed Death 1 Immune Checkpoint Inhibitors

2018 ◽  
Vol 23 (11) ◽  
pp. 1388-1390 ◽  
Author(s):  
Jeremy M. O'Connor ◽  
Kathi Seidl‐Rathkopf ◽  
Aracelis Z. Torres ◽  
Paul You ◽  
Kenneth R. Carson ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Programmed Death ◽  
Programmed Death 1

scholarly journals Acute kidney injury from immune checkpoint inhibitor use

2019 ◽  
Vol 12 (10) ◽  
pp. e231211 ◽  
Author(s):  
Lexis Gordon ◽  
Pouneh Dokouhaki ◽  
Kimberly Hagel ◽  
Bhanu Prasad
Keyword(s):  
Acute Kidney Injury ◽  
Adverse Events ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitor ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitors ◽  
Kidney Injury ◽  
Acute Interstitial Nephritis ◽  
Programmed Death ◽  
Programmed Death 1

Immune checkpoint inhibitors are novel oncological medications, current classes of which include monoclonal antibodies that target inhibitory receptors cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), programmed death 1 protein (PD-1) and programmed death-ligand 1. While they are novel in their ability to treat cancer, they also have a unique spectrum of immune-related adverse events. Renal-related immune adverse events, though rare, are an increasingly recognised clinical entity. We present the case of a 67-year-old man with acute kidney injury (AKI) after the second cycle of combination anti-CTLA-4 and anti-PD-1 antibodies for metastatic cutaneous melanoma. He presented with vomiting and diarrhoea, and AKI secondary to dehydration was treated with aggressive rehydration. After failing to recover biochemically, a renal biopsy was performed, which demonstrated severe acute interstitial nephritis. The culprit medications were held and he was treated with steroids. With immunosuppression, creatinine improved to pretreatment values.

scholarly journals What does PD-L1 positive or negative mean?

2016 ◽  
Vol 213 (13) ◽  
pp. 2835-2840 ◽  
Author(s):  
Antoni Ribas ◽  
Siwen Hu-Lieskovan
Keyword(s):  
Immune Response ◽  
T Cell ◽  
Cancer Cells ◽  
Cell Infiltrate ◽  
Genetic Event ◽  
Programmed Death ◽  
Programmed Death 1 ◽  
Genetic Events

Expression of the programmed death-1 (PD-1) ligand 1 (PD-L1) is used to select patients and analyze responses to anti–PD-1/L1 antibodies. The expression of PD-L1 is regulated in different ways, which leads to a different significance of its presence or absence. PD-L1 positivity may be a result of genetic events leading to constitutive PD-L1 expression on cancer cells or inducible PD-L1 expression on cancer cells and noncancer cells in response to a T cell infiltrate. A tumor may be PD-L1 negative because it has no T cell infiltrate, which may be reversed with an immune response. Finally, a tumor that is unable to express PD-L1 because of a genetic event will always be negative for PD-L1 on cancer cells.

scholarly journals Immune checkpoint inhibitors in renal cell carcinoma

2017 ◽  
Vol 131 (21) ◽  
pp. 2627-2642 ◽  
Author(s):  
Kirsty Ross ◽  
Rob J. Jones
Keyword(s):  
Renal Cancer ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Critical Role ◽  
Optimal Timing ◽  
New Class ◽  
Programmed Death ◽  
Programmed Death 1 ◽  
Immune Manipulation

The immune system has long been known to play a critical role in the body’s defence against cancer, and there have been multiple attempts to harness it for therapeutic gain. Renal cancer was, historically, one of a small number of tumour types where immune manipulation had been shown to be effective. The current generation of immune checkpoint inhibitors are rapidly entering into routine clinical practice in the management of a number of tumour types, including renal cancer, where one drug, nivolumab, an anti-programmed death-1 (PD-1) monoclonal antibody (mAb), is licensed for patients who have progressed on prior systemic treatment. Ongoing trials aim to maximize the benefits that can be gained from this new class of drug by exploring optimal timing in the natural course of the disease as well as combinations with other checkpoint inhibitors and drugs from different classes.

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