Abstract A02: Imprime PGG modulates the myeloid component of the tumor microenvironment to coordinate an antitumor immune response

2016 ◽  
Author(s):  
Kathryn Fraser ◽  
Nadine Ottoson ◽  
Xiaohong Qiu ◽  
Anissa SH Chan ◽  
Adria Jonas ◽  
...  
Keyword(s):  
Immune Response ◽  
Tumor Microenvironment ◽  
Antitumor Immune Response

scholarly journals CD155/CD96 promotes immunosuppression in lung adenocarcinoma (LUAD)

2019 ◽  
Author(s):  
Weiling He ◽  
Hui Zhang ◽  
Shuhua Li ◽  
Yongmei Cui ◽  
Ying Zhu ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Tumor Microenvironment ◽  
Lung Adenocarcinoma ◽  
Cd8 T Cells ◽  
Immune Suppression ◽  
Sodium Dodecyl ◽  
Antitumor Immune Response ◽  
Patient Derived Xenograft ◽  
Poliovirus Receptor

AbstractLung adenocarcinoma (LUAD) remains one of the leading causes of death in patients with cancer. The association of CD155 with CD96 transmits an inhibitory signal and suppresses antitumor immune response. This study investigates the effect of CD155/CD96 on immune suppression in LUAD. We demonstrate that LUAD patients with high CD155 expression suffer from immune suppression and experience a poor prognosis, which coincides with an inhibited AKT-mTOR signaling pathway in CD8 T cells and subsequently up-regulated CD96 expression. Moreover, the inhibition effect can be reversed by CD96 blocking antibody. High CD155 expression inhibited the release of IFNγ from CD8 cells. Moreover, Blocking CD96 restored IFNγ production in CD8 T cells and neutralized the inhibition of IFNγ production in CD8 T cells mediated by CD155. Animal experiments showed that CD155-mediated LUAD growth might depend on its suppression antitumor immune response in the tumor microenvironment in PDX mice. In conclusion, our results suggest that LUAD cells suppress antitumor immune response in the tumor microenvironment through CD155/CD96. CD155/CD96 could be a potential therapeutic target for LUAD patients.AbbreviationsLUAD: lung adenocarcinoma; IFNγ: interferon gamma; PDX: patient-derived xenograft; NSCLC: non-small cell lung cancer; PRR: poliovirus receptor–related; MDSCs: myeloid-derived suppressor cells; PRR: poliovirus receptor–related; STR: short tandem repeat; IRS: immunoreactive score; SI: staining intensity; PP: percentage of positive cells; RT-PCR: reverse transcription-polymerase chain reaction; PBS: phosphate-buffered saline; PBMCs: peripheral blood mononuclear cells; SDS–PAGE: sodium dodecyl sulfate-polyacrylamide gel electrophoresis; rCD155: recombinant human CD155; LUAD cells: lung adenocarcinoma cells; TILs: tumor-infiltrating lymphocytes; GzmB: granzyme B; IL-2 (Interleukin-2); TNF-α : tumor necrosis factor-alpha; PI: propidium Iodide; PDX: patient-derived xenograft; TIGIT: T cell immunoreceptor with Igand ITIM domains; WBC: white blood cells; MFI: mean fluorescence intensity; HPF: high power field

Re-educating the Tumor Microenvironment in the Clinic

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. SCI-48-SCI-48
Author(s):  
Stephen Ansell
Keyword(s):  
Immune Response ◽  
T Cell ◽  
Tumor Microenvironment ◽  
Hodgkin Lymphoma ◽  
Research Funding ◽  
T Regulatory Cells ◽  
Suppressor Cells ◽  
Immune Checkpoint Blockade ◽  
Antitumor Immune Response ◽  
Non Hodgkin Lymphoma

The tumor microenvironment plays a central role in lymphoproliferative disorders and constitution of the microenvironment is associated with patient outcome. Although malignant lymphocytes predominate, cells other than tumor cells are commonly present in malignant lymph nodes. These cells include T lymphocytes, NK cells, dendritic cells and monocytes that seem to be more than simple residual elements from the normal lymph node structure. It is thought that these infiltrating immune cells are part of an antitumor immune response, yet they appear unable to eradicate the malignant clone. Previous studies have shown however that multiple factors present in the tumor microenvironment oppose an effective antitumor immune response. Cells with suppressive function, including T regulatory cells, myeloid derived suppressor cells and suppressive monocytes, are abundant in lymphoma tissue. Suppressive cytokines such as TGFβ and IL-10 are highly expressed in tumors. Furthermore, intratumoral T-cell exhibit an exhausted phenotype with limited proliferation, cytokine production or cytolytic function. Recent therapeutic approaches have focused on overcoming T-cell suppression by activating T-cells or blocking inhibitory signals, thereby re-educating the suppressive tumor microenvironment. Clinical trial results with PD-1 and CTLA-4 directed antibodies in both non-Hodgkin lymphoma and Hodgkin lymphoma have been very promising. Overall response rates particularly in Hodgkin lymphoma patients treated with anti-PD-1 antibodies have been remarkable, although complete responses have been uncommon. Current studies are in progress to confirm the initial results, and further trials will assess the efficacy of immune checkpoint blockade in combination with standard therapies. Disclosures Ansell: Bristol-Myers Squibb: Research Funding; Celldex: Research Funding.

scholarly journals Tumor Microenvironment Immune Response in Pancreatic Ductal Adenocarcinoma Patients Treated With Neoadjuvant Therapy

2020 ◽  
Author(s):  
Theodoros Michelakos ◽  
Lei Cai ◽  
Vincenzo Villani ◽  
Francesco Sabbatino ◽  
Filippos Kontos ◽  
...  
Keyword(s):  
Immune Response ◽  
Tumor Microenvironment ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Neoadjuvant Therapy ◽  
Cell Density ◽  
Antitumor Immune Response ◽  
Ductal Adenocarcinoma ◽  
M2 Macrophage ◽  
Macrophage Density ◽  
Cd8 Cell

Abstract Background Neoadjuvant folinic acid, fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX) and chemoradiation have been used to downstage borderline and locally advanced pancreatic ductal adenocarcinoma (PDAC). Whether neoadjuvant therapy-induced tumor immune response contributes to the improved survival is unknown. Therefore, we evaluated whether neoadjuvant therapy induces an immune response towards PDAC. Methods Clinicopathological variables were collected for surgically resected PDACs at the Massachusetts General Hospital (1998-2016). Neoadjuvant regimens included FOLFIRINOX with or without chemoradiation, proton chemoradiation (25 Gy), photon chemoradiation (50.4 Gy), or no neoadjuvant therapy. Human leukocyte antigen (HLA) class I and II expression and immune cell infiltration (CD4+, FoxP3+, CD8+, granzyme B+ cells, and M2 macrophages) were analyzed immunohistochemically and correlated with clinicopathologic variables. The antitumor immune response was compared among neoadjuvant therapy regimens. All statistical tests were 2-sided. Results Two hundred forty-eight PDAC patients were included. The median age was 64 years and 50.0% were female. HLA-A defects were less frequent in the FOLFIRINOX cohort (P = .006). HLA class II expression was lowest in photon and highest in proton patients (P = .02). The FOLFIRINOX cohort exhibited the densest CD8+ cell infiltration (P < .001). FOLFIRINOX and proton patients had the highest CD4+ and lowest T regulatory (FoxP3+) cell density, respectively. M2 macrophage density was statistically significantly higher in the treatment-naïve group (P < .001) in which dense M2 macrophage infiltration was an independent predictor of poor overall survival. Conclusions Neoadjuvant FOLFIRINOX with or without chemoradiation may induce immunologically relevant changes in the tumor microenvironment. It may reduce HLA-A defects, increase CD8+ cell density, and decrease T regulatory cell and M2 macrophage density. Therefore, neoadjuvant FOLFIRINOX therapy may benefit from combinations with checkpoint inhibitors, which can enhance patients’ antitumor immune response.

scholarly journals IMMU-09. MODULATING THE MYELOID POPULATION IN DIPG MODELS WITH ONCOLYTIC VIRUS AND COMPLEMENT INHIBITORS SHOWS THERAPEUTIC EFFICACY

2021 ◽  
Vol 23 (Supplement_1) ◽  
pp. i28-i29
Author(s):  
Montserrat Puigdelloses ◽  
Virginia Laspidea ◽  
Dolores Hambardzumyan ◽  
Zhihong Chen ◽  
Sumit Gupta ◽  
...  
Keyword(s):  
Immune Response ◽  
Tumor Microenvironment ◽  
Oncolytic Virus ◽  
Continuous Production ◽  
Therapeutic Benefit ◽  
Antitumor Immune Response ◽  
In Vivo Studies ◽  
Immune Memory ◽  
Inflammatory Microenvironment

Abstract Diffuse intrinsic pontine glioma (DIPG) is the leading cause of brain tumor-related death in children. It is characterised for having a non-inflammatory microenvironment and be immunologically inert. Therefore, strategies aiming to break the microenvironment status-quo in this disease could provide therapeutic benefit. The complement system promotes tumor progression due to the continuous production of anaphylatoxins leading to the infiltration of myeloid cells, which express high levels of complement receptors (C3aR and C5aR1). We have in silico data showing the high expression of C5aR1 in DIPGs. Thus, we wanted to assess first whether complement C5aR1 could constitute an actionable target, and second whether combining C5aR1 inhibitors with oncolytic virus could result in a superior antitumor immune response than either agent alone in DIPG. In this study, we used two different peptide inhibitors of C5aR1, PMX53 and PMX205 combined with the virus Delta-24-ACT (an oncolytic virus armed with 4-1BBL). We performed in vivo studies to evaluate the efficacy of this combination in immunocompetent DIPG models. Our data showed that the combination Delta-24-ACT/PMX53 significantly extended the median survival of the animals when compared with either agent alone, and led to long-term survivors that generated immune memory. The combination treatment modulated the tumor microenvironment promoting an increase in lymphocytes, mainly CD8+ cells presenting an active phenotype, and a reduction in C5aR1 expression in the myeloid compartment. We are currently evaluating in vivo whether PMX205, which has an improved ability to cross the blood brain barrier, leads to better therapeutic response. In summary, the combination of Delta-24-ACT with a C5aR1 inhibitor showed the capacity to shake the DIPG tumor microenvironment and unleashed an antitumor immune response. These data underscore the possibilities to combine oncolytic virus with targets of the tumor microenvironment to improve their therapeutic benefit in DIPGs.

scholarly journals Chemotherapeutic and targeted agents can modulate the tumor microenvironment and increase the efficacy of immune checkpoint blockades

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Jun-Yan Li ◽  
Yu-Pei Chen ◽  
Ying-Qin Li ◽  
Na Liu ◽  
Jun Ma
Keyword(s):  
Immune Response ◽  
Tumor Microenvironment ◽  
Combination Therapy ◽  
Immune Checkpoint ◽  
Immune Checkpoint Blockade ◽  
Antitumor Immune Response ◽  
Combination Regimen ◽  
T Cell Infiltration ◽  
Optimal Drug ◽  
Immunosuppressive Cells

AbstractThe development of immune checkpoint blockade (ICB)-based immunotherapy has dramatically changed methods of cancer treatment. This approach triggers a durable treatment response and prolongs patients' survival; however, not all patients can benefit. Accumulating evidence demonstrated that the efficacy of ICB is dependent on a robust antitumor immune response that is usually damaged in most tumors. Conventional chemotherapy and targeted therapy promote the antitumor immune response by increasing the immunogenicity of tumor cells, improving CD8+ T cell infiltration, or inhibiting immunosuppressive cells in the tumor microenvironment. Such immunomodulation provides a convincing rationale for the combination therapy of chemotherapeutics and ICBs, and both preclinical and clinical investigations have shown encouraging results. However, the optimal drug combinations, doses, timing, and sequence of administration, all of which affect the immunomodulatory effect of chemotherapeutics, as well as the benefit of combination therapy, are not yet determined. Future studies should focus on these issues and help to develop the optimal combination regimen for each cancer.

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