Intratumoral T cell infiltration, MHC class I and STAT1 as biomarkers of good prognosis in colorectal cancer

CD8 T cell infiltration of the central nervous system (CNS) is necessary for host protection but contributes to neuropathology. Antigen presenting cells (APCs) situated at CNS borders are thought to mediate T cell entry into the parenchyma during neuroinflammation. The identity of the CNS-resident APC that presents antigen via major histocompatibility complex (MHC) class I to CD8 T cells is unknown. Herein, we characterize MHC class I expression in the naïve and virally infected brain and identify microglia and macrophages (CNS-myeloid cells) as APCs that upregulate H-2Kb and H-2Db upon infection. Conditional ablation of H-2Kb and H-2Db from CNS-myeloid cells allowed us to determine that antigen presentation via H-2Db, but not H-2Kb, was required for CNS immune infiltration during Theiler’s murine encephalomyelitis virus (TMEV) infection and drives brain atrophy as a consequence of infection. These results demonstrate that CNS-myeloid cells are key APCs mediating CD8 T cell brain infiltration.

Download Full-text

Microglia and perivascular macrophages act as antigen presenting cells to promote CD8 T cell infiltration of the brain

10.1101/2021.04.09.439241 ◽

2021 ◽

Author(s):

Emma N Goddery ◽

Cori E Fain ◽

Chloe G Lipovsky ◽

Katayoun Ayasoufi ◽

Lila T Yokanovich ◽

...

Keyword(s):

T Cell ◽

Mhc Class I ◽

Myeloid Cells ◽

Antigen Presenting Cells ◽

Cd8 T Cell ◽

Class I ◽

Cell Infiltration ◽

Host Protection ◽

T Cell Infiltration ◽

Antigen Presenting

CD8 T cell infiltration of the central nervous system (CNS) is necessary for host protection but contributes to neuropathology. Antigen presenting cells (APCs) situated at CNS borders are thought to mediate T cell entry into the parenchyma during neuroinflammation. The identity of the CNS-resident APC that presents antigen via major histocompatibility complex (MHC) class I to CD8 T cells is unknown. Herein, we characterize MHC class I expression in the naive and virally infected brain and identify microglia and macrophages (CNS-myeloid cells) as APCs that upregulate H-2Kb and H-2Db upon infection. Conditional ablation of H-2Kb and H-2Db from CNS-myeloid cells allowed us to determine that antigen presentation via H-2Db, but not H-2Kb, was required for CNS immune infiltration during Theiler′s murine encephalomyelitis virus (TMEV) infection and drives brain atrophy as a consequence of infection. These results demonstrate that CNS-myeloid cells are key APCs mediating CD8 T cell brain infiltration.

Download Full-text

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

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2021-sitc2021.342 ◽

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).

Download Full-text

Tumor microenvironment classification based on T‑cell infiltration and PD‑L1 in patients with mismatch repair‑proficient and ‑deficient colorectal cancer

Oncology Letters ◽

10.3892/ol.2018.9826 ◽

2018 ◽

Author(s):

Shousheng Liu ◽

Pengfei Kong ◽

Xiaopai Wang ◽

Lin Yang ◽

Chang Jiang ◽

...

Keyword(s):

Colorectal Cancer ◽

T Cell ◽

Tumor Microenvironment ◽

Mismatch Repair ◽

Cell Infiltration ◽

T Cell Infiltration

Download Full-text

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

Biomedicine & Pharmacotherapy ◽

10.1016/j.biopha.2019.108921 ◽

2019 ◽

Vol 115 ◽

pp. 108921 ◽

Cited By ~ 11

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

Download Full-text

CD8+ T Cell Co-Expressed Genes Correlate With Clinical Phenotype and Microenvironments of Urothelial Cancer

Frontiers in Oncology ◽

10.3389/fonc.2020.553399 ◽

2020 ◽

Vol 10 ◽

Author(s):

Yutao Wang ◽

Kexin Yan ◽

Jiaxing Lin ◽

Yang Liu ◽

Jianfeng Wang ◽

...

Keyword(s):

Bladder Cancer ◽

T Cells ◽

T Cell ◽

Tumor Microenvironment ◽

Mhc Class I ◽

Clinical Phenotype ◽

Angiogenesis Inhibitors ◽

Class I ◽

T Cell Infiltration ◽

Tumor Purity

PurposeTo identify immune-related co-expressed genes that promote CD8+ T cell infiltration in bladder cancer, and to explore the interactions among relevant genes in the tumor microenvironment.MethodWe obtained bladder cancer gene matrix and clinical information data from TCGA, GSE32894 and GSE48075. The “estimate” package was used to calculate tumor purity and immune score. The CIBERSORT algorithm was used to assess CD8+ T cell proportions. Weighted gene co-expression network analysis was used to identify the co-expression modules with CD8+ T cell proportions and bladder tumor purity. Subsequently, we performed correlation analysis among angiogenesis factors, angiogenesis inhibitors, immune inflammatory responses, and CD8+ T cell related genes in tumor microenvironment.ResultsA CD8+ T cell related co-expression network was identified. Eight co-expressed genes (PSMB8, PSMB9, PSMB10, PSME2, TAP1, IRF1, FBOX6, ETV7) were identified as CD8+ T cell-related genes that promoted infiltration of CD8+ T cells, and were enriched in the MHC class I tumor antigen presentation process. The proteins level encoded by these genes (PSMB10, PSMB9, PSMB8, TAP1, IRF1, and FBXO6) were lower in the high clinical grade patients, which suggested the clinical phenotype correlation both in mRNA and protein levels. These factors negatively correlated with angiogenesis factors and positively correlated with angiogenesis inhibitors. PD-1 and PD-L1 positively correlated with these genes which suggested PD-1 expression level positively correlated with the biological process composed by these co-expression genes. In the high expression group of these genes, inflammation and immune response were more intense, and the tumor purity was lower, suggesting that these genes were immune protective factors that improved the prognosis in patients with bladder cancer.ConclusionThese co-expressed genes promote high levels of infiltration of CD8+ T cells in an immunoproteasome process involved in MHC class I molecules. The mechanism might provide new pathways for treatment of patients who are insensitive to PD-1 immunotherapy due to low degrees of CD8+ T cell infiltration.

Download Full-text