Ablation of interferon regulatory factor 4 in T cells induces “memory” of transplant tolerance that is irreversible by immune checkpoint blockade

Abstract BACKGROUND Glioblastoma (GBM) is associated with systemic and intratumoral immunosuppression. Part of this immunosuppression is mediated by myeloid derived suppressor cells (MDSCs). Preclinical evidence shows that ibrutinib, a tyrosine kinase inhibitor FDA approved for use in chronic lymphocytic leukemia and known to be CNS penetrant, can decrease MDSC generation and function. Also, focal radiation therapy (RT) synergizes with anti-PD-1 therapy in mouse GBM models. Thus, we aimed to test the combination of these approaches on immune activation and survival in a preclinical immune-intact GBM mouse model. METHODS C57BL/6 mice intracranially implanted with the murine glioma cell line GL261-Luc2 were divided into 8 groups consisting of treatments with ibrutinib, RT (10 Gy SRS), or anti-PD-1 individually or in each combination (along with a no treatment control group). Immune cell subset changes (flow-cytometry) and animal survival (Kaplan-Meier) were assessed (n=10 mice per group). RESULTS Median survival of the following groups including control (28 days), ibrutinib (27 days), RT (30 days) or anti-PD-1 (32 days) showed no significant differences. However, a significant improvement in median survival was seen in mice given combinations of ibrutinib+RT (35 days), ibrutinib+anti-PD-1 (38 days), and triple therapy with ibrutinib+RT+anti-PD-1 (48 days, p < 0.05) compared to controls or single treatment groups. The reproducible survival benefit of triple combination therapy was abrogated in the setting of CD4+ and CD8+ T cell depletion. Contralateral intracranial tumor re-challenge in long-term surviving mice suggested generation of tumor-specific immune memory responses. The immune profile of the tumor microenvironment (TME) showed increased cytotoxic CD8+ T cells and decreased MDSCs and regulatory T cells in the triple combination therapy mice compared to controls. CONCLUSION The combination of ibrutinib, focal RT, and anti-PD-1 immune checkpoint blockade led to a significant survival benefit compared to controls in a preclinical model of GBM.

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Abstract B78: Co-potentiation of human T cells to identify subdominant tumor neoantigens from melanoma patients responding to immune checkpoint blockade

10.1158/2326-6074.tumimm18-b78 ◽

2020 ◽

Author(s):

Laura Elsbernd ◽

Alfreda Nelson ◽

Hien Huynh ◽

Michele Hoffmann ◽

Christopher Parks ◽

...

Keyword(s):

T Cells ◽

Immune Checkpoint ◽

Immune Checkpoint Blockade ◽

Checkpoint Blockade ◽

Human T Cells ◽

Melanoma Patients

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Non-conventional Inhibitory CD4+Foxp3–PD-1hi T Cells as a Biomarker of Immune Checkpoint Blockade Activity

Cancer Cell ◽

10.1016/j.ccell.2018.09.007 ◽

2018 ◽

Vol 34 (4) ◽

pp. 691 ◽

Cited By ~ 4

Author(s):

Roberta Zappasodi ◽

Sadna Budhu ◽

Matthew D. Hellmann ◽

Michael A. Postow ◽

Yasin Senbabaoglu ◽

...

Keyword(s):

T Cells ◽

Immune Checkpoint ◽

Immune Checkpoint Blockade ◽

Checkpoint Blockade

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Interferon Regulatory Factor 4 (IRF4) is a Prognostic Marker and Related to Immune Infiltration in Breast and Colorectal Cancers

10.21203/rs.3.rs-39448/v1 ◽

2020 ◽

Author(s):

Qingyan Huang ◽

Zhikang Yu ◽

Yuhong Gan ◽

Heming Wu ◽

Zhixiong Zhong

Keyword(s):

T Cells ◽

Immune Cells ◽

Enrichment Analysis ◽

Interferon Regulatory Factor ◽

Colorectal Cancers ◽

Regulatory Factor ◽

Expression Levels ◽

Immune Infiltration ◽

Prognostic Outcome ◽

Interferon Regulatory Factor 4

Abstract Background: Interferon regulatory factor 4 (IRF4) is a transcription factor that involves in immune cells differentiation. However, it is not clear the relationship between IRF4 and tumor prognosis and immune infiltration.Methods: IRF4 expression levels in different cancers and corresponding normal tissues were analyzed by Oncomine database and Tumor Immune Estimation Resource (TIMER). The prognosis value of IRF4 was assessed by PrognoScan and Kaplan-Meier plotter. The correlation between IRF4 and tumor-infiltrating immune cells and immune cells markers was performed by TIMER and Gene Expression Profiling Interactive Analysis (GEPIA). In addition, we explored the genes regulated by IRF4 in Gene Transcription Regulation Database (GTRD) and then put the above genes in Enrich online tool for Gene Ontology (GO) and pathway enrichment analysis.Results: Decreased expression levels of IRF4 were observed in breast and colorectal cancers. Survival analysis shown that high level of IRF4 was associated with better prognostic outcome in breast and colorectal cancer patients. IRF4 expression was positively correlated with infiltrating levels of B cells, CD8+ T cells, T cells (general), dendritic cells (DCs), Th1, T cell exhaustion and monocytes, and immune cells markers. Beside, functional enrichment analysis of the potential genes regulated by IRF4 indicated that IRF4 may be involved in many important biological processes including immune regulation by regulating various genes.Conclusions: High expression of IRF4 shown better prognostic outcome for breast and colorectal cancers. IRF4 was associated with immune infiltration in breast and colorectal cancers. Therefore, IRF4 maybe serve as a potential prognostic biomarker in breast and colorectal cancers with immune infiltration.

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O4 Mechanisms of lung cancer hyper-progression promoted by PD-1 immune checkpoint blockade

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-itoc7.9 ◽

2020 ◽

Vol 8 (Suppl 2) ◽

pp. A5.1-A5

Author(s):

A Martinez-Usatorre ◽

E Kadioglu ◽

C Cianciaruso ◽

B Torchia ◽

J Faget ◽

...

Keyword(s):

Lung Cancer ◽

T Cells ◽

Regulatory T Cells ◽

Immune Checkpoint ◽

Immune Cell ◽

Immune Checkpoint Blockade ◽

Genetically Engineered ◽

Checkpoint Blockade ◽

Therapeutic Benefits ◽

Angiopoietin 2

BackgroundImmune checkpoint blockade (ICB) with antibodies against PD-1 or PD-L1 may provide therapeutic benefits in patients with non-small cell lung cancer (NSCLC). However, most tumours are resistant and cases of disease hyper-progression have also been reported.Materials and MethodsGenetically engineered mouse models of KrasG12Dp53null NSCLC were treated with cisplatin along with antibodies against angiopoietin-2/VEGFA, PD-1 and CSF1R. Tumour growth was monitored by micro-computed tomography and the tumour vasculature and immune cell infiltrates were assessed by immunofluorescence staining and flow cytometry.ResultsCombined angiopoietin-2/VEGFA blockade by a bispecific antibody (A2V) modulated the vasculature and abated immunosuppressive macrophages while increasing CD8+effector T cells in the tumours, achieving disease stabilization comparable or superior to cisplatin-based chemotherapy. However, these immunological responses were unexpectedly limited by the addition of a PD-1 antibody, which paradoxically enhanced progression of a fraction of the tumours through a mechanism involving regulatory T cells and macrophages. Elimination of tumour-associated macrophages with a CSF1R-blocking antibody induced NSCLC regression in combination with PD-1 blockade and cisplatin.ConclusionsThe immune cell composition of the tumour determines the outcome of PD-1 blockade. In NSCLC, high infiltration of regulatory T cells and immunosuppressive macrophages may account for tumour hyper-progression upon ICB.Disclosure InformationA. Martinez-Usatorre: None. E. Kadioglu: None. C. Cianciaruso: None. B. Torchia: None. J. Faget: None. E. Meylan: None. M. Schmittnaegel: None. I. Keklikoglou: None. M. De Palma: None.

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Radiotherapy-Mediated Immunomodulation and Anti-Tumor Abscopal Effect Combining Immune Checkpoint Blockade

Cancers ◽

10.3390/cancers12102762 ◽

2020 ◽

Vol 12 (10) ◽

pp. 2762 ◽

Cited By ~ 1

Author(s):

Xinrui Zhao ◽

Chunlin Shao

Keyword(s):

T Cells ◽

Cd8 T Cells ◽

Immune Checkpoint ◽

Tumor Regression ◽

Combined Therapy ◽

Immune Checkpoint Blockade ◽

Checkpoint Blockade ◽

Abscopal Effect ◽

Specific Circumstance

Radiotherapy (RT) is a conventional method for clinical treatment of local tumors, which can induce tumor-specific immune response and cause the shrinkage of primary tumor and distal metastases via mediating tumor infiltration of CD8+ T cells. Ionizing radiation (IR) induced tumor regression outside the radiation field is termed as abscopal effect. However, due to the mobilization of immunosuppressive signals by IR, the activated CD8+T cells are not sufficient to maintain a long-term positive feedback to make the tumors regress completely. Eventually, the “hot” tumors gradually turn to “cold”. With the advent of emerging immunotherapy, the combination of immune checkpoint blockade (ICB) and local RT has produced welcome changes in stubborn metastases, especially anti-PD-1/PD-L1 and anti-CTLA-4 which have been approved in clinical cancer treatment. However, the detailed mechanism of the abscopal effect induced by combined therapy is still unclear. Therefore, how to formulate a therapeutic schedule to maximize the efficacy should be took into consideration according to specific circumstance. This paper reviewed the recent research progresses in immunomodulatory effects of local radiotherapy on the tumor microenvironment, as well as the unique advantage for abscopal effect when combined with ICB, with a view to exploring the potential application value of radioimmunotherapy in clinic.

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Absence of central tolerance in Aire-deficient mice synergizes with immune-checkpoint inhibition to enhance antitumor responses

Communications Biology ◽

10.1038/s42003-020-1083-1 ◽

2020 ◽

Vol 3 (1) ◽

Author(s):

Asiel A. Benitez ◽

Sara Khalil-Agüero ◽

Anjali Nandakumar ◽

Namita T. Gupta ◽

Wen Zhang ◽

...

Keyword(s):

T Cells ◽

Immune Checkpoint ◽

Immune Checkpoint Blockade ◽

Tumor Rejection ◽

Checkpoint Blockade ◽

Cell Repertoire ◽

Activated T Cells ◽

Central Tolerance ◽

Tolerance Breakdown ◽

Deficient Mice

AbstractThe endogenous anti-tumor responses are limited in part by the absence of tumor-reactive T cells, an inevitable consequence of thymic central tolerance mechanisms ensuring prevention of autoimmunity. Here we show that tumor rejection induced by immune checkpoint blockade is significantly enhanced in Aire-deficient mice, the epitome of central tolerance breakdown. The observed synergy in tumor rejection extended to different tumor models, was accompanied by increased numbers of activated T cells expressing high levels of Gzma, Gzmb, Perforin, Cxcr3, and increased intratumoural levels of Cxcl9 and Cxcl10 compared to wild-type mice. Consistent with Aire’s central role in T cell repertoire selection, single cell TCR sequencing unveiled expansion of several clones with high tumor reactivity. The data suggest that breakdown in central tolerance synergizes with immune checkpoint blockade in enhancing anti-tumor immunity and may serve as a model to unmask novel anti-tumor therapies including anti-tumor TCRs, normally purged during central tolerance.

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