Faculty Opinions recommendation of A defined commensal consortium elicits CD8 T cells and anti-cancer immunity.

2019 ◽  
Author(s):  
John Nemunaitis ◽  
Laura Stanbery
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Cancer Immunity ◽  
Anti Cancer

scholarly journals A Palette of Cytokines to Measure Anti-Tumor Efficacy of T Cell-Based Therapeutics

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 821
Author(s):  
Prathyaya Ramesh ◽  
Rohan Shivde ◽  
Dinesh Jaishankar ◽  
Diana Saleiro ◽  
I. Caroline Le Poole
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Microenvironment ◽  
Immune Responses ◽  
Cd8 T Cells ◽  
Mechanisms Of Action ◽  
Immune Monitoring ◽  
Cancer Immunity ◽  
Anti Cancer ◽  
Ifn Γ

Cytokines are key molecules within the tumor microenvironment (TME) that can be used as biomarkers to predict the magnitude of anti-tumor immune responses. During immune monitoring, it has been customary to predict outcomes based on the abundance of a single cytokine, in particular IFN-γ or TGF-β, as a readout of ongoing anti-cancer immunity. However, individual cytokines within the TME can exhibit dual opposing roles. For example, both IFN-γ and TGF-β have been associated with pro- and anti-tumor functions. Moreover, cytokines originating from different cellular sources influence the crosstalk between CD4+ and CD8+ T cells, while the array of cytokines expressed by T cells is also instrumental in defining the mechanisms of action and efficacy of treatments. Thus, it becomes increasingly clear that a reliable readout of ongoing immunity within the TME will have to include more than the measurement of a single cytokine. This review focuses on defining a panel of cytokines that could help to reliably predict and analyze the outcomes of T cell-based anti-tumor therapies.

A defined commensal consortium elicits CD8 T cells and anti-cancer immunity

Nature ◽  
2019 ◽  
Vol 565 (7741) ◽  
pp. 600-605 ◽  
Author(s):  
Takeshi Tanoue ◽  
Satoru Morita ◽  
Damian R. Plichta ◽  
Ashwin N. Skelly ◽  
Wataru Suda ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Cancer Immunity ◽  
Anti Cancer

scholarly journals 12P IL-18 improves the anti-cancer immunity of human gamma delta T cells against prostate cancer

2020 ◽  
Vol 31 ◽  
pp. S3-S4
Author(s):  
M.H. Nada ◽  
A.J. Hussein ◽  
H. Wang ◽  
C.T. Morita
Keyword(s):  
Prostate Cancer ◽  
T Cells ◽  
Gamma Delta T Cells ◽  
Gamma Delta ◽  
Cancer Immunity ◽  
Anti Cancer

scholarly journals PD-1-induced T cell exhaustion is controlled by a Drp1-dependent mechanism

2020 ◽  
Author(s):  
Luca Simula ◽  
Valeria Cancila ◽  
Ylenia Antonucci ◽  
Alessandra Colamatteo ◽  
Claudio Procaccini ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Molecular Mechanisms ◽  
Mitochondrial Fission ◽  
Human Colon ◽  
T Cell Response ◽  
Human Colon Cancer ◽  
T Cell Stimulation ◽  
Anti Cancer

AbstractPD-1 signalling downregulates the T cell response, promoting an exhausted state in tumorinfiltrating T cells, through mostly unveiled molecular mechanisms. Drp1-dependent mitochondrial fission plays a crucial role to sustain T cell motility, proliferation, survival and glycolytic engagement and, interestingly, such processes are exactly those inhibited by PD-1 in tumorinfiltrating T cells. Here we show that pD1positive CD8+ T cells infiltrating MC38-derived murine tumor mass show downregulated Drp1 activity and more fused mitochondria compared to PD1negative counterparts. Also, PD1positive lymphocytic elements infiltrating human colon cancer almost never express active Drp1. Mechanistically, PD-1 signaling directly prevents mitochondria fragmentation following T cell stimulation by downregulating Drp1 phosphorylation on Ser616, via regulation of the ERK1/2 pathway and, to a lesser extent, of mTOR. In addition, downregulation of Drp1 activity in tumor-infiltrating PD1positive CD8+ T cells seems to be a mechanism exploited by PD-1 signaling to reduce motility and proliferation of these cells. Overall, our data indicate that the modulation of Drp1 activity in tumor-infiltrating T cells may become a valuable target to ameliorate the anti-cancer immune response in future immunotherapy approaches.

Preclinical efficacy of dendritic cells derived from bone marrow hematopoietic stem cells for the treatment of syngeneic prostate cancer immune cell therapy.

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. 361-361
Author(s):  
Yunlim Kim ◽  
Choung-Soo Kim ◽  
Bongmin Kim
Keyword(s):  
Prostate Cancer ◽  
Stem Cells ◽  
T Cells ◽  
Dendritic Cells ◽  
Cell Therapy ◽  
Cd8 T Cells ◽  
Treated Group ◽  
Hematopoietic Stem ◽  
Anti Cancer ◽  
Ifn Γ

361 Background: PCas are characterized by a primary androgen dependent stage, during which growth is promoted by androgen and suppressed by androgen deprivation or blockade, with even metastatic disease being promptly susceptible to hormonal manipulation; however, despite initial success, androgen deprivation therapy eventually fails because of the development of CRPC. Despite the approval of new clinical trials such as docetaxel, enzalutamide and sipuleucel-T, which is a cell therapy drug, the clinical efficacy is limited. Therefore, there is a desperate need for the limited effectiveness of treatment in an aging society and the development of successful treatments for patients who fail treatment. In this study, we investigated the anticancer effect of prostate cancer using anti-cancer immunity cell vaccine based on the next generation dendritic cell immunotherapy. Methods: FACS and ELISA were performed with stem-DC to analyze phenotype and cytokine expression. To quantify the effect on the tumor growth, we constructed a TRAMP-C1 model and observed for safety, efficacy and induction of antigen-specific immune responses. And we also analyzed proliferation and activation of allogeneic-T cells by therapeutic dendritic cells. Results: From the stem-DC, immune-stimulatory cytokine IL-12 and interferone-gamma was measured higher level than monocyte derived DC (Mo-DC). A DC marker CD11c+CD8a+ cell was higher expression in stem-DC than Mo-DC. After DC injection, tumor size was reduced in stem-DC compared to Mono-DC and vehicle group in TRAMP model. To confirm stem-DC/lysate induce more systemic anti-tumor immunity than Mo-DC/lysate, we checked effector T cells in splenic lymphocytes from prostate cancer bearing mice. The frequency of IFN-γ secreting CD8+ T cells in stem-DC treated group was significantly higher than that in Mo-DC treated group. It shows that the therapeutic responses were associated with induction of IFN-γ secreting CD8+ T cells. Conclusions: Stem-DC, which was developed from hematopoietic stem cells in an optimized manner, proved to be effective and stable as an excellent anti-cancer immunotherapeutic agent for prostate cancer.

807 A multicenter open-label phase I/lb study of SO-C101 as monotherapy and in combination with pembrolizumab in patients with selected advanced/metastatic solid tumors

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A856-A856
Author(s):  
Aurelien Marabelle ◽  
Stephane Champiat ◽  
Elena Garralda ◽  
Alberto Hernando ◽  
Filip Janku ◽  
...  
Keyword(s):  
Clinical Trial ◽  
T Cells ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Dose Escalation ◽  
Cell Activation ◽  
Cd8 T Cell ◽  
Open Label ◽  
Link Type ◽  
Anti Cancer

BackgroundIL-15 is a member of the common y-chain family of cytokines that shares functional activities with IL-2. SO-C101is a superagonist fusion protein of IL-15 and the IL-15 receptor α sushi+ domain. SO-C101 stimulates the proliferation and the cytotoxic activity of NK cells and memory CD8+ T cells.In pre-clinical studies SO-C101 promoted expansion and activation of human, murine and cynomolgus monkey NK and CD8+ T cells. NK and CD8+ T cell activation correlated with potent monotherapy anti-cancer activity of SO-C101 in metastatic and solid tumor models. The combination of an anti-PD-1 or of anti-cancer monoclonal antibodies with SO-C 101 augmented the anti-tumor responses in mouse models. First clinical study was initiated in June 2019 to investigate SO-C101 as monotherapy and in combination with pembrolizumab.MethodsThe phase 1/1 b study currently on-going is a multicenter, open-label, dose escalation study for patients with selected advanced/metastatic solid tumors. The study consists of 2 parts: Part A - dose escalation of SO-C101 as monotherapy; Part B - dose escalation of SO-C101 in combination with pembrolizumab. Study objectives are to define the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of SO-C101 in both parts.ResultsAs of September 22nd, 19 subjects were treated in part A in 6 escalating dose levels, and 3 subjects were treated in part B, at dose level 1.SO-C101 was well tolerated. No DLT was observed, the main AEs related to SO-C101 were injection site reactions, fever, chills, flu-like syndrome, all G1- G2, and transient lymphopenia in 5 subjects, Grade 2 to 4, all resolved within few days.Preliminary PK results showed the PK profile to be dose-proportional, with a Tmax of approx. 5 – 6 hours after administration and T½ approx. 4 hours.Preliminary PD analysis showed dose dependent NK and CD8+ T cell activation.A preliminary efficacy signal has been observed in a patient refractory to anti-PD1 therapy, who showed a RECIST PR with initial 20% shrinkage of target lesions at 6 weeks and 49% shrinkage at 12 weeks on CT-scans.ConclusionsTo date, SO-C101 has been well tolerated, with a manageable toxicity and encouraging signs of clinical activity. The study will proceed to reach a RP2D in both monotherapy and combination with Pembrolizumab. Expansion of the study in selected indications is warranted.Trial Registration https://clinicaltrials.gov/ct2/show/NCT04234113?term=sotio&draw=3&rank=12The study was approved to proceed by FDA – IND 140011 -and by the sites ECs.Ethics ApprovalThe NCT04234113 clinical trial was approved by each investigational site health agency and ethical committee.ConsentWritten informed consent of patients was obtained prior enrollment in the NCT04234113 clinical trial.

Suppression of anti-cancer immunity by regulatory T cells: Back to the future

2006 ◽  
Vol 16 (2) ◽  
pp. 137-149 ◽  
Author(s):  
Rimas J. Orentas ◽  
M. Eric Kohler ◽  
Bryon D. Johnson
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Cancer Immunity ◽  
Anti Cancer ◽  
The Future

scholarly journals Role of Methylation in Pro- and Anti-Cancer Immunity

Cancers ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 545
Author(s):  
Ali Mehdi ◽  
Shafaat A. Rabbani
Keyword(s):  
T Cells ◽  
Transcriptional Regulation ◽  
Immune Cells ◽  
Cell Types ◽  
Rna Methylation ◽  
Dna And Rna ◽  
Cancer Immunity ◽  
Anti Cancer ◽  
And Function

DNA and RNA methylation play a vital role in the transcriptional regulation of various cell types including the differentiation and function of immune cells involved in pro- and anti-cancer immunity. Interactions of tumor and immune cells in the tumor microenvironment (TME) are complex. TME shapes the fate of tumors by modulating the dynamic DNA (and RNA) methylation patterns of these immune cells to alter their differentiation into pro-cancer (e.g., regulatory T cells) or anti-cancer (e.g., CD8+ T cells) cell types. This review considers the role of DNA and RNA methylation in myeloid and lymphoid cells in the activation, differentiation, and function that control the innate and adaptive immune responses in cancer and non-cancer contexts. Understanding the complex transcriptional regulation modulating differentiation and function of immune cells can help identify and validate therapeutic targets aimed at targeting DNA and RNA methylation to reduce cancer-associated morbidity and mortality.

scholarly journals The Impact of Immunofunctional Phenotyping on the Malfunction of the Cancer Immunity Cycle in Breast Cancer

Cancers ◽  
2020 ◽  
Vol 13 (1) ◽  
pp. 110
Author(s):  
Takashi Takeshita ◽  
Toshihiko Torigoe ◽  
Li Yan ◽  
Jing Li Huang ◽  
Hiroko Yamashita ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Low Frequency ◽  
Cytolytic Activity ◽  
Cancer Immunity ◽  
Estrogen Response ◽  
Immunosuppressive Cells ◽  
The Impact

The cancer-immunity cycle (CIC) is a series of self-sustaining stepwise events to fight cancer growth by the immune system. We hypothesized that immunofunctional phenotyping that represent the malfunction of the CIC is clinically relevant in breast cancer (BC). Total of 2979 BC cases; 1075 from TCGA cohort, 1904 from METABRIC cohort were analyzed. The immunofunctional phenotype was classified as follows: hot T-cell infiltrated (HTI), high immune cytolytic activity (CYT), Cold T-cell infiltrated (CTI), high frequency of CD8+ T cells and low CYT, and non-inflamed, low frequency of CD8+ T cells and low CYT. The analysis of tumor immune microenvironment in the immunofunctional phenotype revealed that not only immunostimulatory factors, but also immunosuppressive factors were significantly elevated and immunosuppressive cells were significantly decreased in HTI. Patients in HTI were significantly associated with better survival in whole cohort and patients in CTI were significantly associated with worse survival in triple negative. Furthers, HTI was inversely related to estrogen responsive signaling. We demonstrated that immunofunctional phenotype not only indicated the degree of anti-cancer immune dysfunction, but also served as a prognostic biomarker and HTI was inversely related to estrogen response.

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