scholarly journals Evaluation of the Interplay between the ADAR Editome and Immunotherapy in Melanoma

2021 ◽  
Vol 7 (1) ◽  
pp. 5
Author(s):  
Marina Tusup ◽  
Phil F. Cheng ◽  
Ernesto Picardi ◽  
Austeja Raziunaite ◽  
Reinhard Dummer ◽  
...  
Keyword(s):  
Rna Editing ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Adaptive Immune System ◽  
Rna Seq ◽  
Adaptive Immune ◽  
Histocompatibility Complex ◽  
Anti Cancer ◽  
Transcriptome Diversity

Background: RNA editing is a highly conserved posttranscriptional mechanism that contributes to transcriptome diversity. In mammals, it includes nucleobase deaminations that convert cytidine (C) into uridine (U) and adenosine (A) into inosine (I). Evidence from cancer studies indicates that RNA-editing enzymes promote certain mechanisms of tumorigenesis. On the other hand, recoding editing in mRNA can generate mutations in proteins that can participate in the Major Histocompatibility Complex (MHC) ligandome and can therefore be recognized by the adaptive immune system. Anti-cancer treatment based on the administration of immune checkpoint inhibitors enhance these natural anti-cancer immune responses. Results: Based on RNA-Seq datasets, we evaluated the editome of melanoma cell lines generated from patients pre- and post-immunotherapy with immune checkpoint inhibitors. Our results reveal a differential editing in Arthrobacter luteus (Alu) sequences between samples pre-therapy and relapses during therapy with immune checkpoint inhibitors. Conclusion: These data pave the way towards the development of new diagnostics and therapies targeted to editing that could help in preventing relapses during immunotherapies.

Immune checkpoint and checkpoint inhibitors in hepatocellular carcinoma

2018 ◽  
Vol 1 (1) ◽  
pp. 28-32
Author(s):  
Piyawat Komolmit
Keyword(s):  
Hepatocellular Carcinoma ◽  
T Cells ◽  
Major Histocompatibility Complex ◽  
T Cell Receptor ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Cell Receptor ◽  
Immune Checkpoints ◽  
Histocompatibility Complex

การรักษามะเร็งด้วยแนวความคิดของการกระตุ้นให้ภูมิต้านทานของร่างกายไปทำลายเซลล์มะเร็งนั้น ปัจจุบันได้รับการพิสูจน์ชัดว่าวิธีการนี้สามารถหยุดยั้งการแพร่กระจายของเซลล์มะเร็ง โดยไม่ก่อให้เกิดภาวะแทรกซ้อนทางปฏิกิริยาภูมิต้านทานต่ออวัยวะส่วนอื่นที่รุนแรง สามารถนำมาใช้ทางคลินิกได้ ยุคของการรักษามะเร็งกำลังเปลี่ยนจากยุคของยาเคมีบำบัดเข้าสู่การรักษาด้วยภูมิต้านทาน หรือ immunotherapy ยากลุ่ม Immune checkpoint inhibitors โดยเฉพาะ PD-1 กับ CTLA-4 inhibitors จะเข้ามามีบทบาทในการรักษามะเร็งตับในระยะเวลาอันใกล้ จำเป็นแพทย์จะต้องมีความรู้ความเข้าใจในพื้นฐานของ immune checkpoints และยาที่ไปยับยั้งโมเลกุลเหล่านี้ Figure 1 เมื่อ T cells รับรู้แอนทิเจนผ่านทาง TCR/MHC จะมีปฏิกิริยาระหว่าง co-receptors หรือ immune checkpoints กับ ligands บน APCs หรือ เซลล์มะเร็ง ทั้งแบบกระตุ้น (co-stimulation) หรือยับยั้ง (co-inhibition) TCR = T cell receptor, MHC = major histocompatibility complex

Immune Checkpoint Inhibitors: Basics and Challenges

2019 ◽  
Vol 26 (17) ◽  
pp. 3009-3025 ◽  
Author(s):  
Bin Li ◽  
Ho Lam Chan ◽  
Pingping Chen
Keyword(s):  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Complete Response ◽  
Modern World ◽  
Basic Principles ◽  
Mutation Status ◽  
Anti Cancer ◽  
Cancer Types ◽  
Shed Light

Cancer is one of the most deadly diseases in the modern world. The last decade has witnessed dramatic advances in cancer treatment through immunotherapy. One extremely promising means to achieve anti-cancer immunity is to block the immune checkpoint pathways – mechanisms adopted by cancer cells to disguise themselves as regular components of the human body. Many review articles have described a variety of agents that are currently under extensive clinical evaluation. However, while checkpoint blockade is universally effective against a broad spectrum of cancer types and is mostly unrestricted by the mutation status of certain genes, only a minority of patients achieve a complete response. In this review, we summarize the basic principles of immune checkpoint inhibitors in both antibody and smallmolecule forms and also discuss potential mechanisms of resistance, which may shed light on further investigation to achieve higher clinical efficacy for these inhibitors.

scholarly journals PREDICTIVE RESPONSE MARKERS FOR IMMUNE RESPONSE BLOCKS

2020 ◽  
Vol 19 (4) ◽  
pp. 123-131
Author(s):  
G. A. Janus ◽  
A. G. Ievleva ◽  
E. N. Suspitsyn ◽  
V. I. Tyurin ◽  
I. V. Bizin ◽  
...  
Keyword(s):  
Immune Response ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Predictive Power ◽  
Checkpoint Inhibitors ◽  
Significant Proportion ◽  
Histocompatibility Complex ◽  
Mutation Burden ◽  
Selection Of Patients ◽  
Selection Of

Despite the unprecedented success in using immune checkpoint inhibitors in the treatment of lung cancer, melanoma, hypermutable tumors of various localization, etc., a significant proportion of patients receiving these drugs do not respond to treatment. Predictive markers routinely used in the selection of patients for immunotherapy, in particular, the level of expression of PD -L1 and the presence of microsatellite instability, have certain limitations. Over the past decade, many other biomarkers designed to predict response to immunotherapy have been proposed, namely: tymor mutation burden, composition of lymphocytic infiltrate; allelic composition of the major histocompatibility complex; relationship between the numbers of different formed elements of blood as well as between its biochemical parameters; microflora of the digestive tract, etc. These markers can directly or indirectly reflect the immunogenicity of the tumor itself, as well as the state of systemic and intratumoral immune response. The predictive power and reliability of these markers are extremely different. When preparing this review, we conducted a literature search for recent studies regarding predictors of efficacy for immune checkpoint inhibitors published in the journals included in the databases, such as Pubmed, Web of Science, and Scopus.

scholarly journals Comprehensive Analysis of the Immune Microenvironment Reveals that CD52 is a Marker for Breast Cancer Treatment with Immune Checkpoint Inhibitors

2021 ◽  
Author(s):  
Qiang Wang ◽  
Xuxu Liu ◽  
Pengfei Wang ◽  
Dankun Luo ◽  
Wenqi Gao ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
Cancer Patients ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Adaptive Immune Response ◽  
Breast Cancer Patients ◽  
Immune Microenvironment ◽  
Adaptive Immune

Abstract Background:Breast cancer (BC) is one of the most common tumors in women. Recent years, immune checkpoint inhibitors (ICIs) have brought good news to BC patients. Although significant achievements have been made through treatment with ICIs, some people who experience serious immune-related adverse events (IrAEs) are still insensitive to this approach. The response to ICI treatment depends on the type of tumor microenvironment (TME). Methods:WGCNA (weighted gene co-expression network analysis), ESTIMATE algorithm, LASSO regression analysis, survival analysis, functional enrichment analysis are conducted to analyze the BC data in the TCGA database. Immunohistochemistry was used to verify the expression of CD52 in BC.Results:WGCNA and ESTIMATE algorithm found that the CD52 is closely related to the immune microenvironment. CD52 highly expressed in various breast cancer subtypes, and patients with high expression of CD52 have longer survival time. Compared with the low-CD52 group, the high-CD52 group had more immune cell infiltration. TIMER database verification results showed that CD8+ T cells, activated memory CD4 T cells, memory B cells, γδ T cells, and Tregs were positively correlated with CD52 expression, while M2 macrophages were negatively correlated. CD52 can change the trend of TIC (CD8+ T) and tumor-associated macrophage (TAM) infiltration with respect to the survival time of breast cancer patients. Based on the expression of CD52, we explored the relationship between CD52 and the adaptive immune response (AIR). CD52 is a marker of AIR stratification in breast cancer patients. We constructed a CD52-related adaptive immune response gene signature (CD52rAIRGsig) which is an independent prognostic factor for breast cancer and related to genome instability and the immune cells infiltration in the TME. CD52 and CD52rAIRGsig were associated with PD-1 signaling and immune checkpoint inhibitor markers, which proves that patients with high CD52 expression and low risk of CD52rAIRGsig are more suitable for ICI treatment. We then screened chemotherapeutics for personalized medicine based on CD52rAIRGsig. Conclusion:Therefore, we have discovered a new marker to guide the treatment and prognosis of breast cancer patients with ICIs. This provides a combined treatment strategy including different combinations of ICIs combined with chemotherapeutic drugs to treat breast cancer.

Cell proliferation as a biomarker for response to immune checkpoint inhibitors in highly inflamed renal cell carcinoma.

2019 ◽  
Vol 37 (8_suppl) ◽  
pp. 61-61
Author(s):  
Sarabjot Pabla ◽  
Jason Zhu ◽  
Matthew Labriola ◽  
Rajan Gupta ◽  
Daniel J. George ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Reference Population ◽  
Rna Seq ◽  
Ffpe Tumor ◽  
The Mean ◽  
Immune Related Genes ◽  
Important Marker

61 Background: Cell proliferation is an important marker of survival in many tumors and we hypothesized that this attribute could be related to response to immune checkpoint inhibitors in RCC. Previously we reported (SITC 2018) moderately proliferative lung cancer has a much higher response rate than either poorly or highly proliferative tumors. Methods: 69 FFPE tumor samples of RCC were evaluated by RNA-seq to measure transcript levels of 394 immune related genes, including 10 related to cell proliferation (BUB1, CCNB2, CDK1, CDKN3, FOXM1, KIAA0101, MAD2L1, MELK, MKI67, TOP2A). Cell proliferation, defined as the mean mRNA expression of these 10 genes was evaluated for association with ORR to ICIs by RECIST v1.1 criteria for both PD-L1 IHC positive and negative cases. Cell proliferation for each case was split into 3 tertiles of poorly ( < 33), moderately (33-66) and highly ( > 66) proliferative compared to a reference population. Poorly and highly proliferative were grouped for comparison to moderately proliferative tumors. Tumors were inflamed or non-inflamed based upon RNA‐seq analysis of CD8 compared to a reference population of more than 500 cases of multiple tumors. Non-inflamed, or immune desert tumors, defined as the lower 25th percentile of rank for CD8+ T-cells, and greater than 75th percentile of rank as inflamed. Results: In our cohort of 69 patient the overall ORR was 18.8%. 15.9% of tumors were non-inflamed with an ORR of 9.1%. For 36.2% inflamed tumor the ORR was 32%. For cell proliferation 62.2% were poorly proliferative, 8.7% were highly proliferative, and 29% were moderately. ORR in moderately proliferative tumors was 30% versus 14.2% in poorly/highly proliferative tumors. In inflamed tumors, ORR in moderately proliferative tumors was 37.5% as opposed to 17.6% in poorly/highly proliferative tumors. In 11 non-inflamed tumors, there was only one responder, which was a poorly/highly proliferative tumor. Conclusions: Cell proliferation may play a crucial role in distinguishing RCC patients who may have a clinical benefit to ICI, including the important subgroup of inflamed tumors. Moderately proliferative tumors have a higher ORR than their poorly/highly counterparts.

scholarly journals Sargramostim and immune checkpoint inhibitors: combinatorial therapeutic studies in metastatic melanoma

Immunotherapy ◽  
2021 ◽  
Author(s):  
Ahmad A Tarhini ◽  
Ila Joshi ◽  
Fiona Garner
Keyword(s):  
Immune Responses ◽  
Metastatic Melanoma ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Unmet Needs ◽  
Checkpoint Inhibitors ◽  
Advanced Melanoma ◽  
Clinical Activity ◽  
Gm Csf ◽  
Adaptive Immune

The use of immune checkpoint inhibitors in patients with metastatic melanoma generates clinical benefit, including improved survival. Yet disease resistance and immune-related adverse events persist as unmet needs. Sargramostim, a yeast-derived recombinant human GM-CSF, has shown clinical activity against diverse solid tumors, including metastatic melanoma. Here we review the use of sargramostim for treatment of advanced melanoma. Potential sargramostim applications in melanoma draw on the unique ability of GM-CSF to link innate and adaptive immune responses. We review preclinical and translational data describing the mechanism of action of sargramostim and synergy with immune checkpoint inhibitors to enhance efficacy and reduce treatment-related toxicity.

scholarly journals Toxicity of Immune-Checkpoint Inhibitors in Hematological Malignancies

2021 ◽  
Vol 12 ◽  
Author(s):  
Katarina Hradska ◽  
Roman Hajek ◽  
Tomas Jelinek
Keyword(s):  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Hematological Malignancies ◽  
Checkpoint Inhibitors ◽  
B Cell Lymphoma ◽  
Immune Checkpoint Blockade ◽  
Programmed Death ◽  
Anti Cancer ◽  
Programmed Death 1 ◽  
Insight Into

Immune checkpoint inhibitors (ICIs), especially those targeting the programmed-death 1 (PD-1) receptor and its ligands, have become indispensable agents in solid tumor anti-cancer therapy. Concerning hematological malignancies, only nivolumab and pembrolizumab have been approved for the treatment of relapsed and refractory classical Hodgkin lymphoma and primary mediastinal large B cell lymphoma to date. Nevertheless, clinical research in this field is very active. The mechanism of action of ICIs is based on unblocking the hindered immune system to recognize and eliminate cancer cells, but that also has its costs in the form of ICI-specific immune related adverse events (irAEs), which can affect any organ system and can even be lethal. In this article, we have reviewed all prospective blood cancer clinical trials investigating ICIs (both monotherapy and combination therapy) with available toxicity data with the purpose of determining the incidence of irAEs in this specific setting and to offer a brief insight into their management, as the use of immune checkpoint blockade is not so frequent in hemato-oncology.

scholarly journals Impact of proton therapy on antitumor immune response

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Céline Mirjolet ◽  
Anaïs Nicol ◽  
Emeric Limagne ◽  
Carole Mura ◽  
Corentin Richard ◽  
...  
Keyword(s):  
Immune Response ◽  
Proton Therapy ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Sequencing Analysis ◽  
Rna Seq ◽  
Interferon Signaling ◽  
Functional Profiling ◽  
Photon Radiotherapy

AbstractRadiotherapy delivered using photons induces an immune response that leads to modulation of the tumor microenvironment. Clinical studies are ongoing to evaluate immune checkpoint inhibitors in association with photon radiotherapy. At present, there is no publication on the radio-induced immune response after proton therapy. Balb/c mice bearing subcutaneous CT26 colon tumors were irradiated by a single fraction of 16.4 Gy using a proton beam extracted from a TR24 cyclotron. RNA sequencing analysis was assessed at 3 days post-treatment. Proton therapy immune response was monitored by flow cytometry using several panels (lymphoid, myeloid cells, lymphoid cytokines) at 7 and 14 days post-irradiation. RNA-Seq functional profiling identified a large number of GO categories linked to “immune response” and “interferon signaling”. Immunomonitoring evaluation showed induced tumor infiltration by immune cells. This is the first study showing the effect of proton therapy on immune response. These interesting results provide a sound basis to assess the efficacy of a combination of proton therapy and immune checkpoint inhibitors.

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