scholarly journals 527 Digital spatial profiling of paired tumor biopsies reveals indoleamine 2,3-dioxygenase (IDO)1 as a potential resistance mechanism for a tumor-targeted 4–1BB agonist in patients with solid tumors

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A557-A557
Author(s):  
Tamara Tanos ◽  
Christian Heichinger ◽  
Sabine Wilson ◽  
Marta Canamero ◽  
Mariana Bustamante ◽  
...  
Keyword(s):  
T Cell ◽  
Solid Tumors ◽  
Single Agent ◽  
Resistance Mechanism ◽  
Cd8 T Cell ◽  
Cell Infiltration ◽  
List Type ◽  
T Cell Infiltration ◽  
Spatial Profiling ◽  
Tumor Biopsies

BackgroundWe previously described the capacity of RO7122290 (RO) - a FAP-targeted 4-1BB bispecific antibody - to induce CD8+ T cell infiltration and activation in the tumor (Moreno V. et al, SITC 2020). Aiming to compare pharmacodynamic (PD) changes in tumor nests and stroma, paired tumor biopsies from patients treated with RO (Part A) and RO + atezolizumab (Part B) were analysed by digital spatial profiling (DSP, Nanostring).MethodsSeven paired (baseline and on-treatment) FFPE tumor tissue biopsies (three from Part A, four from Part B) obtained from an ongoing Phase 1/1b trial (EUDRACT 2017-003961-83) were assessed for mRNA and protein expression. Biopsies were taken from six different tumor types at different RO doses. Up to twelve Regions of Interest (ROIs) were collected per slide and the morphology markers PanCK, CD8, CD3 and DAPI were applied. The ROIs were further annotated in tumor nests and stroma segments based on PanCK staining. The immune-oncology 58-plex protein and 78-plex mRNA expression panels (Nanostring) were used to profile all samples. Data were normalized according to Nanostring guidelines and filtered based on relevance (absolute log2 fold change > 1) and significance (FDR < 0.05, p-value).ResultsThe level of CD8+ T cell infiltration measured by spatial profiling correlated with the level measured by IHC, in both tumor nests and stroma. The activation markers 4-1BB and PD-1 were upregulated, confirming the PD effect already measured by mRNA sequencing. We also identified novel protein markers - CD40, PD-L1 and IDO1 - being upregulated after treatment. Spatial regulation differed among the markers with 4-1BB, PD-1 and CD40 upregulated only in the stroma, PD-L1 and IDO1 upregulated in the tumor nests and in the stroma. IDO1 induction is particularly relevant, since this protein is known to attenuate 4-1BB-mediated effector responses. Conventional IHC analysis performed on 14 paired biopsies confirmed IDO1 being upregulated in 11 out of 14 cases and revealed dendritic cells, macrophages and stromal cells to express IDO1. Importantly, IDO1 upregulation was observed in both Part A (3 out of 3) and Part B (8 out of 11).ConclusionsSpatial profiling allowed us to identify key markers that are spatially regulated after treatment and to gain new insights on the MoA of RO. The induction of IDO1 by RO confirms the dual immunoregulatory nature of 4-1BB signaling and highlights IDO1 as a potential resistance mechanism for RO in the clinical setting, both as single agent and in combination with atezolizumab.Trial RegistrationEUDRACT Number: 2017-003961-83; Protocol Number: BP40087ReferencesMoreno V. et al, Pharmacodynamic assessment of a novel FAP-targeted 4–1BB agonist, administered as single agent and in combination with atezolizumab to patients with advanced solid tumors, Nov 1 2020, Journal for ImmunoTherapy of Cancer, presented at SITC 2020

scholarly journals 740 Radiotherapy-activated NBTXR3 nanoparticles Increase CD8+ T cell infiltration and diversity in tumors, and modulate the immunopeptidome of cancer cells

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A771-A771
Author(s):  
Audrey Darmon ◽  
Ping Zhang ◽  
Jordan Da silva ◽  
Sebastien Paris
Keyword(s):  
T Cell ◽  
Cancer Cells ◽  
Single Agent ◽  
Cd8 T Cell ◽  
Cell Infiltration ◽  
Mhc I ◽  
T Cell Infiltration ◽  
Tcr Repertoire ◽  
Repertoire Diversity ◽  
The Impact

BackgroundWhen exposed to radiotherapy (RT), NBTXR3 nanoparticles increase radiation dose deposition from within the cancer cells. NBTXR3 is intended for a single intratumor injection. Results from a phase II/III clinical trial in patients with locally advanced Soft Tissue Sarcoma demonstrated significant superiority and clinical benefits of NBTXR3 activated by RT compared to RT alone, and was well tolerated. NBTXR3 is currently being evaluated in several other tumors including head and neck, liver, and pancreatic cancer as a single agent or in combination with anti-PD1. Moreover, preclinical studies have demonstrated that NBTXR3 can produce a significant abscopal effect, whereas RT alone cannot. Here, we explored the impact of NBTXR3 activated by RT on CD8+ infiltrates and TcR repertoire diversity change, and the effect on the immunopeptidome of cancer cells.MethodsCT26 (murine colorectal cancer cells) were subcutaneously injected in BALB/c mice in one flank. Then, tumors were intratumorally injected with NBTXR3 (or vehicle) and irradiated 24 hours later with 4Gy per fraction for 3 consecutive days. Tumors were collected 3 days after the last RT fraction and immune cell infiltrates were measured using immunohistochemistry (IHC) and digital pathology. For TcR repertoire sequencing, the same workflow was followed, except cells were injected in both flanks. Only right tumors received treatment, while left tumors remained untreated. For immunopeptidome analysis, in vitro cells were irradiated by 4Gy. After one day, cells were collected for isolation and sequencing of MHC I-loaded peptides.ResultsIHC analyses showed a significant increase of CD8+ T cell infiltrates in tumors of mice treated with NBTXR3+RT, while RT alone had no significant effect. In addition, NBTXR3+RT treatment was able to increase TcR repertoire diversity, both in treated and untreated tumors, compared to RT alone. Finally, analysis of immunopeptidome showed that NBTXR3+RT changed the profile of MHC-I-loaded peptides.ConclusionsOur in vivo data indicate that NBTXR3+RT can modulate the microenvironment of treated tumors, leading to enhanced CD8+ T cell infiltration as well as modification of the TcR repertoire, both in treated and distant untreated tumors. These NBTXR3+RT-induced responses may be related to changes in the immunopeptidome of cancer cells triggered by this treatment.

CD8 + T Cell Infiltration Predicts Chemoradiosensitivity in Nasopharyngeal or Oropharyngeal Cancer

2020 ◽  
Vol 131 (4) ◽  
Author(s):  
Toshihiko Kawaguchi ◽  
Takeharu Ono ◽  
Fumihiko Sato ◽  
Akihiko Kawahara ◽  
Tatsuyuki Kakuma ◽  
...  
Keyword(s):  
T Cell ◽  
Oropharyngeal Cancer ◽  
Cd8 T Cell ◽  
Cell Infiltration ◽  
T Cell Infiltration

scholarly journals 342 Combining enadenotucirev and nivolumab increased tumour immune cell infiltration/activation in patients with microsatellite-stable/instability-low metastatic colorectal cancer in a phase 1 study

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A368-A369
Author(s):  
David Krige ◽  
Marwan Fakih ◽  
Lee Rosen ◽  
Ding Wang ◽  
Wael Harb ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
T Cell ◽  
Metastatic Colorectal Cancer ◽  
Cd8 T Cell ◽  
Post Treatment ◽  
Institutional Review Board ◽  
Cell Infiltration ◽  
Link Type ◽  
T Cell Infiltration ◽  
Institutional Review

BackgroundMicrosatellite-stable (MSS) and instability-low (MSI-L) metastatic colorectal cancer (mCRC) are typically characterised as ”immune-excluded/desert” tumour microenvironments lacking T-cell infiltration. Anti-PD-1 monotherapy has little clinical benefit in MSS/MSI-L mCRC1 and knowledge of the effects of PD-1 inhibition on T-cell activation/infiltration in this population is limited. Novel combination therapies to overcome anti-PD-1 resistance are required. SPICE is a multicentre, open-label, phase 1 study of the tumour-selective chimeric Ad11/Ad3 group B oncolytic adenovirus enadenotucirev plus nivolumab in patients with metastatic/advanced epithelial tumours refractory to standard therapy. Preliminary data from patients with MSS/MSI-L mCRC demonstrated a median overall survival of 14 months, manageable tolerability and intratumoural T-cell infiltration.2 Here we characterise the immunological effects of tumour re-engineering with enadenotucirev in combination with nivolumab in patients with MSS/MSI-L mCRC.MethodsPatients received increasing doses and/or cycles of intravenous enadenotucirev followed by up to 8 cycles of nivolumab as previously described.2 Wherever possible, pre- and post-treatment (~5 weeks post-first enadenotucirev) biopsies were collected; samples were analysed using immunohistochemistry and automated image analysis. Peripheral blood mononuclear cell immunophenotyping (multiparameter flow cytometry) and serum cytokines were assessed at multiple times.Results43 patients with mCRC were treated (86% MSS/MSI-L; 14% unknown). Among the 13 patients (12/13 MSS/MSI-L; 1/13 unknown) with matched biopsies, 11 had increased intratumoural and stromal CD8+ T-cell infiltration in post-treatment biopsies (median [Q1-Q3] fold changes 6.5× [1.5–25.4] and 1.9× [1.5–3.9], respectively; figure 1). CD4+ T-cell density increased in 10/13 patients and 8/13 patients had increased proportions of PD-L1+ immune cells. Increases in CD8 T-cell proliferation (Ki67; 7/9 patients) and cytolytic activity (Granzyme B; 7/13 patients) markers were seen. 4/13 patients converted from a ”desert” to an ”inflamed” immune phenotype (pathologist scored CD8/pan-cytokeratin staining). Immunophenotyping showed trends towards increased T-cell activation (CD38+ and HLA-DR+ CD8+ T cell populations) post-treatment (9/10 patients), including in one patient who had only received enadenotucirev prior to sampling. Persistent increases in inflammatory cytokines (IFNγ, IL-12p70, IL-17a) were seen in two patients from ~Day 15, including one who achieved a sustained objective response.Abstract 342 Figure 1Tumour immune cell infiltration following treatment with enadenotucirev plus nivolumabConclusionsThese data show that intravenous enadenotucirev plus nivolumab can induce immune infiltration/activation within MSS/MSI-L mCRC. These encouraging findings suggest that immune activation can be achieved even in ”immune-excluded/desert” tumours. SPICE has been closed following completion of dose-escalation. Efforts are now focused on the development of next-generation variants of enadenotucirev designed to further re-programme the tumour microenvironment by expressing immune-enhancer transgenes (T-SIGn vectors); these studies are ongoing (NCT04830592, NCT04053283, NCT03852511).AcknowledgementsThis study was funded by PsiOxus Therapeutics Limited and Bristol Myers Squibb. Medical writing support: Lola Parfitt, MRes, of PsiOxus Therapeutics Limited.Trial RegistrationEudraCT number2017-001231-39NCT number: NCT02636036ReferencesKawazoe A, Kuboki Y, Shinozaki E, et al. Multicenter phase I/II trial of napabucasin and pembrolizumab in patients with metastatic colorectal cancer (EPOC1503/SCOOP trial). Clin Cancer Res 2020;26:5887–5894.Fakih M, Wang D, Harb W, et al. SPICE: a phase I multicenter study of enadenotucirev in combination with nivolumab in tumors of epithelial origin: an analysis of the metastatic colorectal cancer patients in the dose escalation phase. Ann Oncol 2019:30(suppl_5):v252.Ethics ApprovalThe study was approved by the WCG Institutional Review Board (study approval number 20152656), UCLA Institutional Review Board (study approval number IRB#15-002010), Vanderbilt Institutional Review Board (study approval number IRB #171453) and Henry Ford Institutional Review Board (study approval number IRB #10349).

scholarly journals Updates on Immunotherapy and Immune Landscape in Renal Clear Cell Carcinoma

Cancers ◽  
2021 ◽  
Vol 13 (22) ◽  
pp. 5856
Author(s):  
Myung-Chul Kim ◽  
Zeng Jin ◽  
Ryan Kolb ◽  
Nicholas Borcherding ◽  
Jonathan Alexander Chatzkel ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Cells ◽  
Immune Cell ◽  
Single Cell Analysis ◽  
Clear Cell ◽  
Cd8 T Cell ◽  
Cell Infiltration ◽  
Cellular Mechanisms ◽  
T Cell Infiltration ◽  
Immunological Mechanisms

Several clinicopathological features of clear cell renal cell carcinomas (ccRCC) contribute to make an “atypical” cancer, including resistance to chemotherapy, sensitivity to anti-angiogenesis therapy and ICIs despite a low mutational burden, and CD8+ T cell infiltration being the predictor for poor prognosis–normally CD8+ T cell infiltration is a good prognostic factor in cancer patients. These “atypical” features have brought researchers to investigate the molecular and immunological mechanisms that lead to the increased T cell infiltrates despite relatively low molecular burdens, as well as to decipher the immune landscape that leads to better response to ICIs. In the present study, we summarize the past and ongoing pivotal clinical trials of immunotherapies for ccRCC, emphasizing the potential molecular and cellular mechanisms that lead to the success or failure of ICI therapy. Single-cell analysis of ccRCC has provided a more thorough and detailed understanding of the tumor immune microenvironment and has facilitated the discovery of molecular biomarkers from the tumor-infiltrating immune cells. We herein will focus on the discussion of some major immune cells, including T cells and tumor-associated macrophages (TAM) in ccRCC. We will further provide some perspectives of using molecular and cellular biomarkers derived from these immune cell types to potentially improve the response rate to ICIs in ccRCC patients.

scholarly journals Spatiotemporal single-cell profiling of gastrointestinal GVHD reveals invasive and resident memory T cell states

2020 ◽  
Author(s):  
Victor Tkachev ◽  
James Kaminski ◽  
E. Lake Potter ◽  
Scott N. Furlan ◽  
Alison Yu ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Single Cell ◽  
Cd8 T Cell ◽  
Transcriptomic Analysis ◽  
Cell Infiltration ◽  
Cell Transplant ◽  
Gi Tract ◽  
Tissue Invasion ◽  
T Cell Infiltration

ABSTRACTOne of the central challenges in the field of allo-immunity is deciphering the mechanisms driving T cells to infiltrate and subsequently occupy target organs to cause disease. The act of CD8-dominated T cell infiltration is critical to acute graft-versus-host disease (aGVHD), wherein donor T cells become activated, tissue-infiltrating and highly cytotoxic, causing wide-spread tissue damage after allogeneic hematopoietic stem cell transplant (allo-HCT). However, in human and non-human primate studies, deconvolving the transcriptional programs of newly recruited relative to resident memory T cells in the gastrointestinal (GI) tract has remained a challenge. In this study, we combined the novel technique of Serial Intravascular Staining (SIVS) with single-cell RNA-Seq (scRNA-seq) to enable detailed dissection of the tightly connected processes by which T cells first infiltrate tissues and then establish a pathogenic tissue residency program after allo-HCT in non-human primates. Our results have enabled the creation of a spatiotemporal map of the transcriptional drivers of CD8 T cell infiltration into the primary aGVHD target-organ, the GI tract. We identify the large and small intestines as the only two sites demonstrating allo-specific, rather than lymphdepletion-driven T cell infiltration. The donor CD8 T cells that infiltrate the GI tract demonstrate a highly activated, cytotoxic phenotype while simultaneously rapidly developing canonical tissue-resident memory (TRM) protein expression and transcriptional signatures, driven by IL-15/IL-21 signaling. Moreover, by combining SIVS and transcriptomic analysis, we have been able to work backwards from this pathogenic TRM programing, and, for the first time, identify a cluster of genes directly associated with tissue invasiveness, prominently including specific chemokines and adhesion molecules and their receptors, as well as a central cytoskeletal transcriptional node. The clinical relevance of this new tissue invasion signature was validated by its ability to discriminate the CD8 T cell transcriptome of patients with GI aGVHD. These results provide new insights into the mechanisms controlling tissue infiltration and pathogenic CD8 TRM transcriptional programing, uncovering critical transitions in allo-immune tissue invasion and destruction.One sentence summaryFlow cytometric and transcriptomic analysis reveals coordinated tissue-infiltration and tissue-residency programs driving gastrointestinal aGVHD.

scholarly journals Intrinsic β-catenin signaling suppresses CD8+ T-cell infiltration in colorectal cancer

2019 ◽  
Vol 115 ◽  
pp. 108921 ◽  
Author(s):  
Junli Xue ◽  
Xuetao Yu ◽  
Liqiong Xue ◽  
Xiaoxiao Ge ◽  
Wei Zhao ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
T Cell ◽  
Cd8 T Cell ◽  
Cell Infiltration ◽  
T Cell Infiltration

scholarly journals Lymphatic vessel density is associated with CD8+ T cell infiltration and immunosuppressive factors in human melanoma

2018 ◽  
pp. e1462878 ◽  
Author(s):  
Natacha Bordry ◽  
Maria A. S. Broggi ◽  
Kaat de Jonge ◽  
Karin Schaeuble ◽  
Philippe O. Gannon ◽  
...  
Keyword(s):  
T Cell ◽  
Lymphatic Vessel ◽  
Cd8 T Cell ◽  
Human Melanoma ◽  
Vessel Density ◽  
Cell Infiltration ◽  
Lymphatic Vessel Density ◽  
T Cell Infiltration ◽  
Immunosuppressive Factors

T1906 CD8+ T Cell Infiltration and Cancer Recrurrence in Squamous Cell Cancer of the Anus

2008 ◽  
Vol 134 (4) ◽  
pp. A-893
Author(s):  
Sonia Ramamoorthy ◽  
Katsumi N. Miyai ◽  
Linda Luo ◽  
John M. Carethers
Keyword(s):  
T Cell ◽  
Squamous Cell ◽  
Squamous Cell Cancer ◽  
Cell Cancer ◽  
Cd8 T Cell ◽  
Cell Infiltration ◽  
T Cell Infiltration
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