scholarly journals Vγ9Vδ2 T Cells as Strategic Weapons to Improve the Potency of Immune Checkpoint Blockade and Immune Interventions in Human Myeloma

2018 ◽  
Vol 8 ◽  
Author(s):  
Barbara Castella ◽  
Assunta Melaccio ◽  
Myriam Foglietta ◽  
Chiara Riganti ◽  
Massimo Massaia
Keyword(s):  
T Cells ◽  
Immune Checkpoint ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Vγ9vδ2 T Cells

Immune Checkpoint Blockade Combinations As Promising Strategy for Cancer Immunotherapy in Multiple Myeloma Patients

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2059-2059 ◽  
Author(s):  
Barbara Castella ◽  
Myriam Foglietta ◽  
Patrizia Sciancalepore ◽  
Ezio Tripoli ◽  
Mario Boccadoro ◽  
...  
Keyword(s):  
T Cells ◽  
Immune Checkpoint ◽  
Research Funding ◽  
Single Agent ◽  
Immune Checkpoint Blockade ◽  
Advisory Board ◽  
Checkpoint Blockade ◽  
Immune Checkpoints ◽  
Myeloma Cells ◽  
Vγ9vδ2 T Cells

Abstract Tumor cells exploit immune checkpoints to withstand immune recognition and effector cells' onslaught. Pre-clinical findings, corroborated by initial results of clinical studies, indicate that immune checkpoint blockade is a promising strategy to harness anti-tumor immune responses and improve the clinical outcome of patients with hematological malignancies. Multiple myeloma (MM) is a prototypic disease in which immune checkpoints significantly contribute to the immune suppressive contexture that myeloma cells establish in the bone marrow (BM) in cooperation with regulatory T cells (Tregs), myeloid derived suppressor cells (MDSC), and BM stromal cells (BMSC). Vγ9Vδ2 T cells are among the immune effector cells strategically victimized by suppressor cells. These are non-conventional T cells halfway between innate and adaptive immunity with a natural inclination to react against malignant B cells, including myeloma cells. Vγ9Vδ2 T cells are equipped with a peculiar array of receptors for stress-induced self-ligands and a unique TCR-dependent recognition ability of phosphoantigens (pAgs) generated in the mevalonate (Mev) pathway. Recently, we have shown that BM Vγ9Vδ2 T cells are anergic to pAg stimulation and that the programmed death 1(PD-1)/programmed death ligand 1 (PD-L1) immune checkpoint pair contributes to their dysfunction. This is an early event already detectable in individuals with monoclonal gammopathy of undetermined significance (MGUS) and not fully reverted even when MM patients achieve clinical remission after autologous stem cell transplantation (auto-SCT). Anti-PD-1 treatment partially recovers the ability of BM Vγ9Vδ2 T cells to proliferate and exert cytotoxic activity after pAg stimulation, but early studies based on single-agent PD-1 blockade have fallen short of clinical expectations in MM. Thus, several strategies are under consideration to implement the clinical efficacy of immune checkpoint blockade like the association with lenalidomide and/or concurrent tumor vaccination. Our results indicate that TIM-3 is significantly upregulated in BM Vγ9Vδ2 T cells from MM patients at diagnosis. We have previously shown that pAg stimulation of PD-1+ BM Vγ9Vδ2 T cells further increase PD-1 expression and preliminary data suggest that this stimulation also increases TIM-3 expression. Interestingly, TIM-3 up-regulation is even more pronounced than PD-1 up-regulation in BM Vγ9Vδ2 T cells and it occurs also in peripheral blood (PB) Vγ9Vδ2 T cells from anergic MM patients. We have recently shown that pAg reactivity of BM Vγ9Vδ2 T cells from MM at diagnosis can be partially recovered by PD-1 blockade. Our results reveal that TIM-3 blockade is also able to partially recover pAg-induced Vγ9Vδ2 T-cell proliferation. The best recovery is obtained when pAg stimulation is carried out in the presence of concurrent PD-1 and TIM-3 blockade. BM Vγ9Vδ2 T cells from MM patients who are in remission (MM-rem) after auto-SCT are still PD1+ and anergic to pAg stimulation. Remarkably, percentages of PD-L1+ MDSC in the BM of MM-rem are also unchanged compared to MM at diagnosis (MM-dia) and MM in relapse (MM-rel). These data indicate that the immune suppressive contexture is still operative at the tumor site even when most of myeloma cells have been cleared by chemotherapy. Interestingly, chemoresistant residual myeloma cells after auto-SCT have been reported to be PD-L1+, and circulating exhausted PD-1+ CD8+ T cells have been described in the PB after auto-SCT. This may explain why our previous idiotype vaccination studies in MM patients have failed. We have initiated to investigate the effect of immune checkpoint blockade in different phases of the disease and preliminary results suggest that the functional outcome of PD-1 blockade can be very different according to the disease status: the most signifcant recovery of Vγ9Vδ2 T-cell proliferation is observed after PD-1 blockade in MM-rem, while the anergy of Vγ9Vδ2 T cells from MM-rel is totally refractory to immune checkpoint blockade. In conclusion, our results suggest that recovery of pAg reactivity by PB Vγ9Vδ2 T cells is a reliable biomarker to predict or assess the clinical efficacy of immune checkpoint in vivo and provide scientific groundwork to optimize anti-PD1 treatment as single agent or in combination with other antibodies (i.e, anti-TIM-3) to maximize the efficacy of immune checkpoint blockade according to the disease status. Disclosures Boccadoro: Amgen: Honoraria, Research Funding; SANOFI: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Mundipharma: Research Funding; Janssen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; CELGENE: Honoraria, Research Funding; Abbivie: Honoraria. Massaia:Roche: Other: advisory board, research support; Janssen: Other: advisory board; Gilead: Other: advisory board.

scholarly journals Immune checkpoint blockade impairs immunosuppressive mechanisms of regulatory T cells in B-cell lymphoma

2021 ◽  
Vol 14 (9) ◽  
pp. 101170
Author(s):  
Vera Bauer ◽  
Fatima Ahmetlić ◽  
Nadine Hömberg ◽  
Albert Geishauser ◽  
Martin Röcken ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
B Cell ◽  
Immune Checkpoint ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade

scholarly journals IMMU-19. TARGETING GLIOBLASTOMA IMMUNOSUPPRESSION AND TREATMENT RESISTANCE WITH IBRUTINIB IN COMBINATION WITH STEREOTACTIC RADIATION AND IMMUNE CHECKPOINT BLOCKADE

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii108-ii108
Author(s):  
Jayeeta Ghose ◽  
Baisakhi Raychaudhuri ◽  
Kevin Liu ◽  
William Jiang ◽  
Pooja Gulati ◽  
...  
Keyword(s):  
T Cells ◽  
Combination Therapy ◽  
Median Survival ◽  
Immune Checkpoint ◽  
Survival Benefit ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Control Group ◽  
Triple Combination ◽  
Triple Combination Therapy

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.

scholarly journals 836 Releasing the restraints of Vγ9Vδ2 T-cells in cancer immunotherapy

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A888-A888
Author(s):  
Laura Ridgley ◽  
Angus Dalgleish ◽  
Mark Bodman-Smith
Keyword(s):  
T Cells ◽  
Cancer Immunotherapy ◽  
Tumour Cell ◽  
Immune Checkpoint ◽  
Expansion Method ◽  
Immune Checkpoint Blockade ◽  
Immune Checkpoints ◽  
Inhibitory Receptors ◽  
Healthy Donors ◽  
Vγ9vδ2 T Cells

BackgroundVγ9Vδ2 T-cells are a subset of cells with a crucial role in immunosurveillance which can be activated and expanded by multiple means to stimulate effector responses, often exploited in cancer immunotherapy. Little is known about the expression of checkpoint molecules on this cell population and whether the ligation of these molecules can regulate their activity. The aim of this study was to assess the expression of activatory and inhibitory markers on Vγ9Vδ2 T-cells to assess potential avenues of regulation to target with immunotherapy.MethodsPBMCs were isolated from healthy donors and the expression of activatory and inhibitory receptors was assessed on Vγ9Vδ2 T-cells by flow cytometry at baseline, following 24 hours activation and 14 days expansion using zoledronic acid (ZA) and Bacillus Calmette-Guerin (BCG), both with IL-2. Activation and expansion of Vδ2 cells was assessed by expression of CD69 and by frequency of Vδ2 cells, respectively. Production of effector molecules was also assessed following coculture with various tumour cell targets. The effect of immune checkpoint blockade on Vγ9Vδ2 T-cells was also assessed.ResultsVγ9Vδ2 T-cells constitutively expressed high levels of NK-associated activatory markers NKG2D and DNAM1 which remained high following stimulation with ZA and BCG. Vγ9Vδ2 T-cells expressed variable levels of checkpoint inhibitor molecules at baseline with high levels of BTLA, KLRG1 and NKG2A and intermediate levels of PD1, TIGIT and VISTA. Expression of checkpoint receptors were modulated following activation and expansion with ZA and BCG with decreased expression of BTLA and upregulation of numerous markers including PD1, TIGIT, TIM3, LAG3 and VISTA. Expression of these markers is further modulated upon coculture with tumour cell lines with changes reflecting activation of these cells with Vγ9Vδ2 T-cells expressing inhibitory receptors PD1 and NKG2A producing the highest level of TNF.ConclusionsOur data reveals unique characteristics of Vδ2 in terms of their expression of immune checkpoints, which provide a mechanism which may be utilised by tumour cells to subvert Vγ9Vδ2 T-cell cytotoxicity. Our work suggests different profiles of immune checkpoints dependent on the method of stimulation. This highlights importance of expansion method in the function of Vγ9Vδ2 T-cells. Furthermore, this work suggests important candidates for blockade by immune checkpoint therapy in order to increase the successful use of Vγ9Vδ2 T-cells in cancer immunotherapy.

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

Cancer Cell ◽  
2018 ◽  
Vol 34 (4) ◽  
pp. 691 ◽  
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

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

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.

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

Cancers ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 2762 ◽  
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.

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

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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