scholarly journals Opposing Functions of Interferon Coordinate Adaptive and Innate Immune Responses to Cancer Immune Checkpoint Blockade

Cell ◽  
2019 ◽  
Vol 178 (4) ◽  
pp. 933-948.e14 ◽  
Author(s):  
Joseph L. Benci ◽  
Lexus R. Johnson ◽  
Ruth Choa ◽  
Yuanming Xu ◽  
Jingya Qiu ◽  
...  
Keyword(s):  
Immune Responses ◽  
Immune Checkpoint ◽  
Immune Checkpoint Blockade ◽  
Innate Immune ◽  
Checkpoint Blockade ◽  
Innate Immune Responses

scholarly journals IMMU-09. CONCURRENT DEXAMETHASONE LIMITS THE CLINICAL BENEFIT OF IMMUNE CHECKPOINT BLOCKADE IN GLIOBLASTOMA

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii106-ii106
Author(s):  
Bryan Iorgulescu ◽  
Prafulla Gokhale ◽  
Maria Speranza ◽  
Benjamin Eschle ◽  
Michael Poitras ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Immune Checkpoint ◽  
Nk Cell ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Innate Immune Responses ◽  
Dose Dependent Fashion ◽  
Dexamethasone Therapy ◽  
Clinical Correlate ◽  
Dose Dependent

Abstract BACKGROUND Dexamethasone, a uniquely potent corticosteroid, is frequently administered to brain tumor patients to decrease tumor-associated edema, but limited data exist describing how dexamethasone affects the immune system systemically and intratumorally in glioblastoma patients – particularly in the context of immunotherapy. METHODS We evaluated the dose-dependent effects of dexamethasone when administered with anti-PD-1 and/or radiotherapy in immunocompetent C57BL/6 mice with syngeneic GL261 or CT-2A glioblastoma tumors, including analyses of intracranial tumors, draining lymph nodes, and spleen. Clinically, the effect of dexamethasone on survival was additionally evaluated in 181 consecutive IDH-wildtype glioblastoma patients treated with anti-PD-(L)1, with adjustment for relevant prognostic factors. RESULTS Despite the inherent responsiveness of GL261 to immune checkpoint blockade, concurrent dexamethasone administration with anti-PD-1 therapy decreased survival in a dose-dependent fashion and decreased survival following anti-PD-1 plus radiotherapy in both GL261 and immunoresistant CT-2A models. Dexamethasone quantitatively decreased T lymphocytes by reducing the proliferation while increasing apoptosis. Dexamethasone also decreased lymphocyte functional capacity. Myeloid and NK cell populations were also generally reduced. Thus, dexamethasone negatively affects both the adaptive and innate immune responses. As a clinical correlate, a retrospective analysis of 181 consecutive IDH-wildtype glioblastoma patients treated with PD-(L)1 blockade revealed worse survival among those on baseline dexamethasone. Upon multivariable adjustment with relevant prognostic factors, baseline dexamethasone use – regardless of dose – was the strongest predictor of poor survival (reference no dexamethasone; < 2mg HR 2.28, 95%CI=1.41–3.68, p=0.001; ≥2mg HR 1.97, 95%CI=1.27–3.07, p=0.003). CONCLUSIONS Our preclinical and clinical data indicate that concurrent dexamethasone therapy may be detrimental to immunotherapeutic approaches for glioblastoma patients. Our preclinical analyses also suggest that dexamethasone’s detrimental effects are dose-dependent, suggesting that the lowest possible dose should be used for patients when dexamethasone use is unavoidable. Careful evaluation of dexamethasone use is warranted for neuro-oncology patients undergoing immunotherapy clinical trials.

EXTH-08. STAT3 AT THE CROSSROADS OF INNATE IMMUNE ACTIVATION IN GLIOBLASTOMA

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi164-vi165
Author(s):  
Christina von Roemeling ◽  
Lan Hoang-Minh ◽  
Bently Doonan ◽  
Chenglong Li ◽  
Duane Mitchell
Keyword(s):  
Immune Suppression ◽  
Immune Cells ◽  
Immune Checkpoint ◽  
Myeloid Cells ◽  
Suppressor Cells ◽  
Immune Checkpoint Blockade ◽  
Innate Immune ◽  
Checkpoint Blockade ◽  
Tumor Bearing ◽  
Stat3 Inhibition

Abstract BACKGROUND Innate immune cells comprise the majority of the immune microenvironment in glioblastoma (GBM) tumors where they are chiefly thought to foster a hospitable environment for cancer cells by regulating immune suppression and driving resistance to immunotherapy. Of these, myeloid-derived suppressor cells (MDSCs) are regarded as one of the most potent contributors to immune suppression in GBM and thus have become a focus of targeted therapy. Signal transducer and activator of transcription 3 (STAT3) is a key phenotypic regulator of MDSCs. Therefore, we sought to examine if targeted STAT3 inhibition may augment the immunogenicity of these tumors. HYPOTHESIS: Targeted STAT3 inhibition reduces GBM tumor infiltration by MDSCs. METHODS Using syngeneic murine models of GBM, we performed pharmacological inhibition analyses using a specific small molecule inhibitor of STAT3, LLL12B. Circulating numbers of immune cells were assessed in tumor bearing animals with or without concomitant focal radiation. Treated tumors were examined for immune infiltrates, and additional phenotyping analyses were performed. Therapeutic responses to LLL12B alone and in combination with immune checkpoint blockade were evaluated. RESULTS STAT3 is activated in the bone marrow of tumor-bearing animals, preferentially by Gr-1 positive granulocytic myeloid cells. Increased circulating numbers of these cells were also detected. These observations were markedly enhanced in tumor-bearing animals following cranial irradiation. Therapeutic inhibition with LLL12B could mitigate these effects, indicating a dependency on STAT3. Within the tumor compartment, granulocytic myeloid cells that successfully infiltrated following treatment demonstrated a pro-inflammatory phenotype denoted by interferon-gamma expression. Improved survival was also observed following combination treatment with LLL12B and radiation or immune checkpoint blockade. CONCLUSIONS These findings advocate a critically important role for STAT3 in regulating granulocytic myeloid cell mobilization and trafficking to GBM tumors. It further illustrates the plasticity of these cells within these tumors, which may be useful in designing successful immunotherapeutic strategies.

scholarly journals Dynamics of Tumor and Immune Responses during Immune Checkpoint Blockade in Non–Small Cell Lung Cancer

2018 ◽  
Vol 79 (6) ◽  
pp. 1214-1225 ◽  
Author(s):  
Valsamo Anagnostou ◽  
Patrick M. Forde ◽  
James R. White ◽  
Noushin Niknafs ◽  
Carolyn Hruban ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Immune Responses ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Immune Checkpoint ◽  
Immune Checkpoint Blockade ◽  
Small Cell ◽  
Checkpoint Blockade ◽  
Small Cell Lung

scholarly journals The Role of Immune Checkpoint Receptors in Regulating Immune Reactivity in Lupus

Cells ◽  
2019 ◽  
Vol 8 (10) ◽  
pp. 1213 ◽  
Author(s):  
Kun-Lin Lu ◽  
Ming-Ying Wu ◽  
Chi-Hui Wang ◽  
Chuang-Wei Wang ◽  
Shuen-Iu Hung ◽  
...  
Keyword(s):  
Immune Responses ◽  
Signaling Pathways ◽  
Lupus Erythematosus ◽  
Immune Checkpoint ◽  
Past Research ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Immune Reactivity ◽  
Recent Success ◽  
Checkpoint Receptors

Immune checkpoint receptors with co-stimulatory and co-inhibitory signals are important modulators for the immune system. However, unrestricted co-stimulation and/or inadequate co-inhibition may cause breakdown of self-tolerance, leading to autoimmunity. Systemic lupus erythematosus (SLE) is a complex multi-organ disease with skewed and dysregulated immune responses interacting with genetics and the environment. The close connections between co-signaling pathways and SLE have gradually been established in past research. Also, the recent success of immune checkpoint blockade in cancer therapy illustrates the importance of the co-inhibitory receptors in cancer immunotherapy. Moreover, immune checkpoint blockade could result in substantial immune-related adverse events that mimic autoimmune diseases, including lupus. Together, immune checkpoint regulators represent viable immunotherapeutic targets for the treatment of both autoimmunity and cancer. Therefore, it appears reasonable to treat SLE by restoring the out-of-order co-signaling axis or by manipulating collateral pathways to control the pathogenic immune responses. Here, we review the current state of knowledge regarding the relationships between SLE and the co-signaling pathways of T cells, B cells, dendritic cells, and neutrophils, and highlight their potential clinical implications. Current clinical trials targeting the specific co-signaling axes involved in SLE help to advance such knowledge, but further in-depth exploration is still warranted.

scholarly journals Macrophage-Derived CXCL9 and CXCL10 Are Required for Antitumor Immune Responses Following Immune Checkpoint Blockade

2019 ◽  
Vol 26 (2) ◽  
pp. 487-504 ◽  
Author(s):  
Imran G. House ◽  
Peter Savas ◽  
Junyun Lai ◽  
Amanda X.Y. Chen ◽  
Amanda J. Oliver ◽  
...  
Keyword(s):  
Immune Responses ◽  
Immune Checkpoint ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade
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