Cancer Biomarkers: Tumor-Infiltrating T Cells, Programmed Death-Ligand 1, and Tumor Mutation Burden

2021 ◽  
Author(s):  
Colt Egelston ◽  
Weihua Guo ◽  
Peter P. Lee
Keyword(s):  
T Cells ◽  
Cancer Biomarkers ◽  
Tumor Mutation Burden ◽  
Programmed Death Ligand 1 ◽  
Mutation Burden ◽  
Programmed Death

The Immunobiology of Kidney Cancer

2018 ◽  
Vol 36 (36) ◽  
pp. 3547-3552 ◽  
Author(s):  
Charles G. Drake ◽  
Mark N. Stein
Keyword(s):  
Kidney Cancer ◽  
Immune Checkpoint Blockade ◽  
Antiangiogenic Agents ◽  
Tumor Mutation Burden ◽  
Programmed Death Ligand 1 ◽  
T Cell Infiltration ◽  
Mutation Burden ◽  
Programmed Death ◽  
Programmed Death 1 ◽  
Tumor Types

Although kidney cancer (renal cell carcinoma [RCC]) is susceptible to immunotherapy, the immunologic aspects of the tumor microenvironment (TME) in RCC are relatively unique among tumor types. In RCC, baseline CD8 T-cell infiltration is associated with a worse prognosis. In addition, kidney cancer responds to programmed death-1/programmed death-ligand 1 blockade, despite a relatively low tumor mutation burden. Recent clinical data highlight the efficacy of combined immune checkpoint blockade and demonstrate that combining antiangiogenic agents with programmed death-1/programmed death-ligand 1 blockade has additive activity. Yet an important unanswered question in RCC is the nature of the antigens that are targeted by the immune system when immunotherapy is successful. Ongoing clinical studies are interrogating the multiple suppressive mechanisms in the RCC TME, including metabolic pathways such as those mediated by adenosine and tryptophan as well as cytokine-based therapies. Future regimens are likely to be combinatorial and may eventually be based on a broader understanding of the RCC TME and how it is modulated by both conventional and immune-based therapy.

scholarly journals Recurrent Gallbladder Carcinoma With pMMR/MSS Achieved a Complete Response Following Camrelizumab Combined With Apatinib: A Case Report

2022 ◽  
Vol 11 ◽  
Author(s):  
Liting Zhong ◽  
Xiaoyu Liu ◽  
Zelei Li ◽  
Xuebing Zhang ◽  
Yuli Wang ◽  
...  
Keyword(s):  
Gallbladder Carcinoma ◽  
Complete Response ◽  
Limited Data ◽  
Effective Treatment Option ◽  
Tumor Mutation Burden ◽  
Angiogenic Therapy ◽  
Mutation Burden ◽  
Programmed Death ◽  
Programmed Death 1 ◽  
Durable Complete Response

Gallbladder carcinoma (GBC) with proficient mismatch repair (pMMR)/microsatellite stable (MSS) is associated with limited response to programmed death-1 (PD-1) inhibitor monotherapy. Limited data of PD-1 blockade combined with anti-angiogenic therapy in GBC are reported. One recurrent GBC patient with pMMR/MSS was treated with camrelizumab plus apatinib. After 4 cycles of combination therapy, the patient achieved a durable complete response with manageable toxicity. The next-generation sequencing and immunohistochemistry analysis showed that tumor mutation burden (TMB) was 7.26 mutants/Mb and PD-L1 expression was 10% (tumor proportion score) and 20% (immune proportion score). This case suggests that camrelizumab in combination with apatinib may be an effective treatment option for GBC patients with pMMR/MSS status, who have moderate expression of TMB and PD-L1. Additionally, TMB and PD-L1 expression may serve as potential biomarkers for predicting PD-1 inhibitor response of GBC. Furthermore, this needs to be verified in future studies.

scholarly journals Regulatory T Cells and Human Myeloid Dendritic Cells Promote Tolerance via Programmed Death Ligand-1

PLoS Biology ◽  
2010 ◽  
Vol 8 (2) ◽  
pp. e1000302 ◽  
Author(s):  
Shoba Amarnath ◽  
Carliann M. Costanzo ◽  
Jacopo Mariotti ◽  
Jessica L. Ullman ◽  
William G. Telford ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Regulatory T Cells ◽  
Myeloid Dendritic Cells ◽  
Programmed Death Ligand 1 ◽  
Programmed Death

Antigen-Specific Transfer of Functional Programmed Death Ligand 1 From Antigen Presenting Cells Onto Human CD8+ T Cells Via Trogocytosis

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 584-584
Author(s):  
Regina Gary ◽  
Simon Voelkl ◽  
Ralf Palmisano ◽  
Andreas Mackensen
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
T Cell Responses ◽  
Antigen Presenting Cells ◽  
Programmed Death Ligand 1 ◽  
Cell Responses ◽  
Surface Molecules ◽  
Programmed Death ◽  
Antigen Presenting

Abstract Abstract 584 Specific T-cell responses are initiated by T-cell receptor (TCR) recognition of peptide-MHC-complexes on antigen presenting cells (APCs). Upon specific interaction of T cells with APCs T cells capture membrane fragments and surface molecules of APCs in a process termed trogocytosis. Exchange of membrane molecules/antigens between immune cells has been observed for a long time, but the mechanisms and functional consequences of these transfers remain unclear. Here, we demonstrate that human antigen-specific CD8+ T cells do acquire the co-inhibitory molecule programmed death ligand 1 (PD-L1) from mature monocyte-derived dendritic cells (mDC) and tumor cells in an antigen-specific manner. The kinetics of PD-L1 transfer revealed a maximal PD-L1 expression on antigen-specific T cells within 3–4 hours after co-incubation with antigen-pulsed APCs, being detectable up to 72 hours. Antigen-pulsed immature DCs were less effective in transfering surface molecules such as PD-L1 onto CD8+ T cells after antigen-specific recognition. Using a transwell system we could show that the acquisition of PD-L1 requires cell-cell contact. Furthermore, PD-L1 cannot be acquired by T cells from a lysate of mDCs. The transfer process is impaired after pretreatment of T cells with concanamycin A, a specific inhibitor of vacuolar ATPases, playing an important role in membrane trafficking. Moreover, fixation of DCs with glutaraldehyde completely abrogated the acquisition of PD-L1 on T cells suggesting that an active interaction between APCs and T cells is required for trogocytosis. Of importance, CD8+ T cells which acquired PD-L1 complexes, were able to induce apoptosis of neighbouring PD-1 expressing CD8+ T cells, that could be completely blocked by an anti-PD-L1 antibody. In summary our data demonstrate for the first time that human antigen-specific CD8+ T cells take up functionally active PD-L1 from APCs in an antigen-specific fashion, leading to apoptosis of PD-1 expressing T cells. The transfer of functionally active co-inhibitory molecules from APCs onto human CD8+ T cells may serve to limit clonal expansion of antigen-specific T-cell responses but may also play a major role for T-cell exhaustion in chronic infection and tumor immunosurveillance. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Kaposi’s Sarcoma-Associated Herpesvirus Increases PD-L1 and Proinflammatory Cytokine Expression in Human Monocytes

mBio ◽  
2017 ◽  
Vol 8 (5) ◽  
Author(s):  
Kurtis M. Host ◽  
Sarah R. Jacobs ◽  
John A. West ◽  
Zhigang Zhang ◽  
Lindsey M. Costantini ◽  
...  
Keyword(s):  
T Cells ◽  
Proinflammatory Cytokine ◽  
Kaposi's Sarcoma ◽  
Primary Effusion Lymphoma ◽  
Kaposi’S Sarcoma ◽  
Lymphoproliferative Disorders ◽  
Human Monocytes ◽  
Programmed Death Ligand 1 ◽  
Kshv Infection ◽  
Programmed Death

ABSTRACTKaposi’s sarcoma-associated herpesvirus (KSHV) is associated with the human malignancy Kaposi’s sarcoma and the lymphoproliferative disorders primary effusion lymphoma and multicentric Castleman’s disease. KSHV establishes lytic infection of monocytesin vivo, which may represent an important cellular reservoir during KS disease progression. KS tumors consist of latently infected endothelial cells; however, lytic phase gene products are important for KS onset. Early KS lesion progression is driven by proinflammatory cytokines supplied by immune cell infiltrates including T cells and monocytes. KSHV-infected monocytes may supply the lytic viral products and the inflammatory milieu conducive to KS tumor progression. To establish successful infection, KSHV extensively modulates the host immune system. KSHV antigens activate both innate and adaptive immune responses including KSHV-specific T cells, but lifelong infection is still established. Programmed death ligand 1 (PD-L1) is a prosurvival cell surface protein that suppresses T-cell-mediated killing. PD-L1 is variably present on various tumor cells and is a targetable marker for cancer treatment. We show that KSHV infection of human monocytes increases PD-L1 expression and transcription in a dose-dependent manner. We also saw evidence of lytic gene expression in the KSHV-infected monocytes. Intact KSHV is needed for full PD-L1 response in human monocytes. KSHV induces a general proinflammatory cytokine milieu including interleukins 1α, 1β, and 6, which have been implicated in early KS lesion progression. KSHV-mediated PD-L1 increase may represent a novel mechanism of KSHV-mediated immune modulation to allow for virus survival and eventually malignant progression.IMPORTANCEKSHV is the etiologic agent of Kaposi’s sarcoma and the lymphoproliferative disorders primary effusion lymphoma and multicentric Castleman’s disease. Programmed death ligand 1 (PD-L1) is an immunosuppressive cell surface marker that inhibits T cell activation. We report that KSHV infection of primary human monocytes upregulates PD-L1 transcription and protein expression. Analysis of the cytokine and chemokine milieu following KSHV infection of monocytes revealed that KSHV induces interleukins 1α, 1β, and 6, all of which have been implicated in KS development. Our work has identified another potential immune evasion strategy for KSHV and a potential target for immunotherapy of KSHV-derived disease.

scholarly journals Programmed Death Ligand 1 Is Expressed by Non–Hodgkin Lymphomas and Inhibits the Activity of Tumor-Associated T Cells

2011 ◽  
Vol 17 (13) ◽  
pp. 4232-4244 ◽  
Author(s):  
David J. Andorsky ◽  
Reiko E. Yamada ◽  
Jonathan Said ◽  
Geraldine S. Pinkus ◽  
David J. Betting ◽  
...  
Keyword(s):  
T Cells ◽  
Programmed Death Ligand 1 ◽  
Programmed Death

scholarly journals Defining muscle-invasive bladder cancer immunotypes by introducing tumor mutation burden, CD8+ T cells, and molecular subtypes

Hereditas ◽  
2021 ◽  
Vol 158 (1) ◽  
Author(s):  
Zihao Chen ◽  
Guojun Liu ◽  
Guoqing Liu ◽  
Mikhail A. Bolkov ◽  
Khyber Shinwari ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
T Cells ◽  
Signaling Pathway ◽  
Cd8 T Cells ◽  
Molecular Subtypes ◽  
Molecular Subtype ◽  
Muscle Invasive Bladder Cancer ◽  
Tumor Mutation Burden ◽  
Mutation Burden ◽  
Muscle Invasive

AbstractImmunotherapy, especially anti-PD-1, is becoming a pillar of modern muscle-invasive bladder cancer (MIBC) treatment. However, the objective response rates (ORR) are relatively low due to the lack of precise biomarkers to select patients. Herein, the molecular subtype, tumor mutation burden (TMB), and CD8+ T cells were calculated by the gene expression and mutation profiles of MIBC patients. MIBC immunotypes were constructed using clustering analysis based on tumor mutation burden, CD8+ T cells, and molecular subtypes. Mutated genes, enriched functional KEGG pathways and GO terms, and co-expressed network-specific hub genes have been identified. We demonstrated that ORR of immunotype A patients identified by molecular subtype, CD8+ T cells, and TMB is about 36% predictable. PIK3CA, RB1, FGFR3, KMT2C, MACF1, RYR2, and EP300 are differentially mutated among three immunotypes. Pathways such as ECM-receptor interaction, PI3K-Akt signaling pathway, and TGF-beta signaling pathway are top-ranked in enrichment analysis. Low expression of ACTA2 was associated with the MIBC survival benefit. The current study constructs a model that could identify suitable MIBC patients for immunotherapy, and it is an important step forward to the personalized treatment of bladder cancers.

scholarly journals MUC4 mutation correlates with tumor mutation burden and the immune microenvironment in colorectal cancer

2020 ◽  
Author(s):  
Ting Li ◽  
Wenjia Hui ◽  
Halina Halike ◽  
Feng Gao
Keyword(s):  
Colorectal Cancer ◽  
Immune Response ◽  
T Cells ◽  
Immune Cells ◽  
Gene Mutations ◽  
Cancer Genome ◽  
Immune Microenvironment ◽  
Tumor Mutation Burden ◽  
Mutation Burden ◽  
Mutant Genes

Abstract Background: Immunotherapy is a new strategy for Colorectal cancer (CRC) treatment. Tumor mutation burden (TMB) may act as an emerging biomarker for predicting responses to immunotherapy. Nevertheless, no studies investigate if these gene mutations correlate to TMB and tumor-infiltrating immune cells. Methods: Somatic mutation data for CRC samples were obtained from The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC) datasets. Then, we investigated the relationship between these mutant genes, TMB and overall survival outcomes. GSEA analysis was performed to explore the underlying mechanism of mutant gene. Finally, we further verified the connection between gene mutations and immune response.Results: We identified 17 common mutant genes shared by both two cohorts. Further analysis found that MUC4 mutation was strongly related to higher TMB and predicted a poorer prognosis. Moreover, functional enrichment analysis of samples with MUC4 mutation revealed that they were involved in regulating the natural killer cell mediated cytotoxicity signaling pathway. Significant changes in the proportion of the immune cells of CD8 T cells, activated NK cells, M1 macrophages and resting memory CD4 T cells were observed using the CIBERSORT algorithm. Conclusions: Our research revealed that MUC4 mutation significantly correlated with increased TMB, a worse prognosis and modulating the immune microenvironment, which may be considered a biomarker to predict the outcome of the immune response in colorectal cancer.

Translational research of voltage-A1: Efficacy predictors of preoperative chemoradiotherapy and subsequent nivolumab monotherapy in patients with microsatellite-stable locally advanced rectal cancer.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 4073-4073 ◽  
Author(s):  
Koji Inamori ◽  
Yosuke Togashi ◽  
Hideaki Bando ◽  
Yuichiro Tsukada ◽  
Ayako Suzuki ◽  
...  
Keyword(s):  
Rectal Cancer ◽  
T Cells ◽  
T Cell ◽  
Mononuclear Cells ◽  
Locally Advanced ◽  
Tumor Regression Grade ◽  
Ki67 Expression ◽  
Tumor Mutation Burden ◽  
Cell Ratio ◽  
Mutation Burden

4073 Background: In VOLTAGE-A1, after 5 cycles of nivolumab (240 mg q2 weeks) plus radical surgery following chemoradiotherapy (CRT; 50.4 Gy with capecitabine 1,650 mg/m2), a major pathologic response is observed in 38% (AJCC tumor regression grade 0-1) of 37 patients with microsatellite-stable locally advanced primary rectal cancer. Here, biomarkers for predicting the efficacy of this treatment were investigated. Methods: Serial tumor biopsies and blood collections were performed at 4 time points; before CRT, after CRT, after 3 cycles of nivolumab, and before surgery. Tumor-infiltrating lymphocytes (TILs) and DNA/RNA were extracted from tumor samples, and peripheral blood mononuclear cells (PBMCs) were extracted from blood samples. We analyzed the immune status of the patients by flow cytometry using the collected TILs and PBMCs. Whole exome and RNA sequencing analyses were conducted using the extracted DNA and RNA, respectively. The PD-L1 status of tumor samples was also evaluated by in vitro diagnostic immunohistochemistry staining. Results: Among the 24 patients whose samples were serially collected, 11 (46%) were AJCC grade 0-1 and 13 were 2-3. Before CRT, effector regulatory T (eTreg) cells in TILs were higher in patients with AJCC grade 2-3, and both the CD8+ T cell/eTreg cell ratio in TILs and PD-L1-positive tumor cells (≥1%) were higher in patients with AJCC grade 0-1 (p = 0.047, p = 0.083, respectively). Ki67 expression by CD8+ T cells in TILs was higher before CRT in patients with AJCC grade 0-1 (p = 0.037) and increased after CRT in all patients. Patients with consensus molecular subtype (CMS) 1 and CMS3 achieved AJCC grade 0-1 at rates of 100% (2/2) and 60% (4/6), respectively. In contrast, patients with CMS2 and CMS4 achieved AJCC grade 0-1 at rates of 43% (3/7) and 29% (2/7), respectively. The tumor mutation burden of pre-CRT samples was significantly higher in patients with AJCC grade 0-1 (median 1.45/MB) than in patients with AJCC grade 2-3 (0.84/MB) (p = 0.016). Conclusions: A higher CD8+ T cell/eTreg cell ratio, PD-L1-positive, Ki67 expression by CD8+ T cells in TILs, CMS1 or 3, and higher tumor mutation burden are good predictors of the efficacy of the sequential combination of CRT and nivolumab. Further results will be reported in the meeting. Clinical trial information: NCT02948348 .

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