scholarly journals The proposed promiscuity value of an HLA can vary significantly depending on the source data used

2021 ◽  
Author(s):  
Jordan Anaya ◽  
Alexander S. Baras
Keyword(s):  
T Cells ◽  
Immune System ◽  
Cancer Cells ◽  
Immune Checkpoint ◽  
Peptide Binding ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Data Types ◽  
Patient Response ◽  
Source Data

ABSTRACTImmune checkpoint blockade, a form of immunotherapy, mobilizes a patient’s own immune system against cancer cells by releasing some of the natural brakes on T cells. Although our understanding of this process is evolving, it is thought that a patient response to immunotherapy requires tumor presentation of neoantigens to T cells and patients whose tumors present a wider array of neoantigens are more likely to derive benefit from immune checkpoint blockade1–4. Manczinger et al.5 recently reported findings that would appear contrarian to this notion in that they suggested patients with HLA alleles which bind more diverse peptides (higher promiscuity) are less likely to respond to immunotherapy. To estimate HLA promiscuity they looked at the HLA-peptide binding repertoires for class I alleles contained in the IEDB6, and obtained consistent results when performing robustness checks and subsequent analyses. Here we show that the proposed HLA promiscuity values can vary significantly across source data types and individual experiments.

scholarly journals PREDICTIVE IMMUNE CHECKPOINT BLOCKADE CLASSIFIERS DISTINGUISHING MONO- VERSUS COMBINATION THERAPY REQUIREMENT

2020 ◽  
Author(s):  
Oscar Krijgsman ◽  
Kristel Kemper ◽  
Julia Boshuizen ◽  
David W. Vredevoogd ◽  
Elisa A. Rozeman ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Cell ◽  
Immune Checkpoint ◽  
Human Tumor ◽  
Immune Checkpoint Blockade ◽  
Adoptive Cell Transfer ◽  
Checkpoint Blockade ◽  
Melanoma Tumor ◽  
Extrinsic Factors ◽  
Patient Response

Although high clinical response rates are seen for immune checkpoint blockade (ICB) treatment of metastatic melanomas, both intrinsic and acquired ICB resistance remain considerable clinical challenges1. Combination ICB (anti-PD-1 + anti-CTLA-4) shows improved patient benefit2–5, but is associated with severe adverse events and exceedingly high cost. Therefore, there is a dire need to stratify individual patients for their likelihood of responding to either anti-PD-1 or anti-CTLA-4 monotherapy, or the combination. Since it is conceivable that ICB responses are influenced by both tumor cell-intrinsic and -extrinsic factors6–9, we hypothesized that a predictive genetic classifier ought to mirror both these features. In a panel of patient-derived melanoma xenografts10 (PDX), we noted that cells derived from the human tumor microenvironment (TME) that were co-grafted with the tumor cells were naturally replaced by murine cells after the first passage. Taking advantage of the XenofilteR11 algorithm we recently developed to deconvolute human from murine RNA sequence reads from PDX10, we obtained curated human melanoma tumor cell RNA reads. These expression signals were computationally subtracted from the total RNA profiles in bulk (tumor cell + TME) melanomas from patients. We thus derived one genetic signature that is purely tumor cell-intrinsic (“InTumor”), and one that comprises tumor cell-extrinsic RNA profiles (“ExTumor”). Here we report that the InTumor signature predicts patient response to anti-PD-1, but not anti-CTLA-4 treatment. This was validated in melanoma PDX and cell lines, which confirmed that InTumorLO tumors were effectively eliminated by adoptive cell transfer of T-Cell Receptor (TCR)-matched cytotoxic T cells, whereas InTumorHI melanomas were refractory and grew out as fast as tumors challenged with unmatched T cells. In contrast, the ExTumor signature predicts patient response to anti-CTLA-4 but not anti-PD-1. Most importantly, we used the InTumor and ExTumor signatures in conjunction to generate an ICB response quadrant, which predicts clinical benefit for five independent melanoma patient cohorts treated with either mono- or combination ICB. Specifically, these signatures enable identification of patients who have a much higher chance of responding to the combination treatment than to either monotherapy (p < 0.05), as well as patients who are likely to experience little benefit from receiving anti-CTLA-4 on top of anti-PD-1 (p < 0.05). These signatures may be clinically exploited to distinguish patients who need combined PD-1 + CTLA-4 blockade from those who are likely to benefit from either anti-CTLA-4 or anti-PD-1 monotherapy.

scholarly journals IMMU-15. ENGINEERED-DRUG RESISTANT GAMMA-DELTA (γδ) T CELLS COMBINED WITH IMMUNE CHECKPOINT BLOCKADE AUGMENTED KILLING OF CANCER CELLS

2018 ◽  
Vol 20 (suppl_6) ◽  
pp. vi124-vi124
Author(s):  
Sailesh Gopalakrishna Pillai ◽  
Yancey Gillespie ◽  
Cathy Langford ◽  
Samantha Langford ◽  
Trent Spencer ◽  
...  
Keyword(s):  
T Cells ◽  
Cancer Cells ◽  
Immune Checkpoint ◽  
Γδ T Cells ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Drug Resistant ◽  
Gamma Delta

scholarly journals 62 Identify immune cell types and biomarkers associated with immune-related adverse events using single cell RNA sequencing

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A67-A67
Author(s):  
Jiamin Chen ◽  
Lance Pflieger ◽  
Sue Grimes ◽  
Tyler Baker ◽  
Michael Brems ◽  
...  
Keyword(s):  
Colon Cancer ◽  
T Cells ◽  
Immune System ◽  
Adverse Events ◽  
Single Cell ◽  
Immune Checkpoint ◽  
Inflammatory Responses ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Single Cell Rna Sequencing

BackgroundRecent advancements in immunotherapy are revolutionizing the landscape of clinical immuno-oncology and have significantly increased patient survival in a range of cancers. Notably, immune checkpoint blockade therapies have induced durable responses and provided tremendous clinical benefits to previously untreatable patients. However, unleashing immune system against cancer also disrupts the immunologic homeostasis and induce inflammatory responses, resulting immune-related adverse events. The precise mechanisms underlying immune-related adverse events (irAEs) remain unknown. Furthermore, it is unclear why immune checkpoint blockade therapies only induce irAEs in some patients but not the others. In this study, we systematically characterize the functional impacts of immune checkpoint blockade on the patient immune system at single-cell resolution.MethodsThe peripheral blood mononuclear cells (PBMCs) from seven cancer patients with melanoma, non-small cell lung cancer, or colon cancer (MSI-H) receiving immune checkpoint inhibitors (CPIs), i.e. anti–PD-1+anti-CTLA4 combo or anti-PD-1 single agent, were collected at three serial time points (T1, T2, and T3). During the immunotherapy, four patients developed irAEs, including colitis (2X), pneumonitis (1), hyper/hypothyroidism (1), while three patients showed no signs of irAEs. In total, we generated and characterized single cell gene expression profiles for more than 65,000 cells from 21 PBMC libraries. Furthermore, we simultaneously measured TCR and BCR from nine selected samples, thus generating a comprehensive profile of Immune repertoire upon CPIs.ResultsWe systematically characterized T cells, B cells, monocytes, NK cells, and platelets from PBMCs. Both checkpoint blockade and patient comorbidity affect PBMC populations. We found that irAEs are often associated with an acute increase in monocytes and decrease in T cells. After repeated CPI treatment, PBMC populations remained relatively stable. We characterized specific subsets within each cell type that are associated with CPI treatment as well as patient clinical conditions, and identified signature genes for each subset. For example, Mucosal-Associated Invariant CD8 T cells were strongly enriched in the PBMC population of the colon cancer patient. In the melanoma patient who received anti–PD-1+anti-CTLA4 combo but didn’t develop colitis, we found enriched NK cell subsets expressing chemokine such as XCL1 and CCL4. Furthermore, we found prominent T cell clonal expansion in this patient compared to the two melanoma patients who developed colitis. The administration of steroids after irAEs led to massive anti-inflammatory responses in PMBCs, often characterized by the prominent expression of AREG.ConclusionsOur study characterized the functional impact of CPIs on patient PBMCs. Our data demonstrated that single cell RNA sequencing provides a powerful tool to dissect and identify clinically actionable biomarkers for response prediction and side effects alleviation in patients receiving immunotherapy in the era of precision medicine.Ethics ApprovalThis study was approved by the Institutional Review Board (#1050678) at Intermountain Healthcare (Salt Lake City, UT USA)

scholarly journals A bilateral tumor model identifies transcriptional programs associated with patient response to immune checkpoint blockade

2020 ◽  
Vol 117 (38) ◽  
pp. 23684-23694
Author(s):  
Ivy X. Chen ◽  
Kathleen Newcomer ◽  
Kristen E. Pauken ◽  
Vikram R. Juneja ◽  
Kamila Naxerova ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Immune Checkpoint ◽  
Predictive Biomarkers ◽  
Tumor Model ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Patient Response ◽  
Bilateral Tumor

Immune checkpoint blockade (ICB) is efficacious in many diverse cancer types, but not all patients respond. It is important to understand the mechanisms driving resistance to these treatments and to identify predictive biomarkers of response to provide best treatment options for all patients. Here we introduce a resection and response-assessment approach for studying the tumor microenvironment before or shortly after treatment initiation to identify predictive biomarkers differentiating responders from nonresponders. Our approach builds on a bilateral tumor implantation technique in a murine metastatic breast cancer model (E0771) coupled with anti-PD-1 therapy. Using our model, we show that tumors from mice responding to ICB therapy had significantly higher CD8+T cells and fewer Gr1+CD11b+myeloid-derived suppressor cells (MDSCs) at early time points following therapy initiation. RNA sequencing on the intratumoral CD8+T cells identified the presence of T cell exhaustion pathways in nonresponding tumors and T cell activation in responding tumors. Strikingly, we showed that our derived response and resistance signatures significantly segregate patients by survival and associate with patient response to ICB. Furthermore, we identified decreased expression of CXCR3 in nonresponding mice and showed that tumors grown inCxcr3−/−mice had an elevated resistance rate to anti-PD-1 treatment. Our findings suggest that the resection and response tumor model can be used to identify response and resistance biomarkers to ICB therapy and guide the use of combination therapy to further boost the antitumor efficacy of ICB.

Potential immunotherapy for Alzheimer disease and age-related dementia

2019 ◽  
Vol 21 (1) ◽  
pp. 21-25 ◽  
Keyword(s):  
Immune System ◽  
Alzheimer Disease ◽  
Cross Talk ◽  
Immune Checkpoint ◽  
Short Review ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
New Approach ◽  
Age Related ◽  
The Brain

Emerging results support the concept that Alzheimer disease (AD) and age-related dementia are affected by the ability of the immune system to contain the brain's pathology. Accordingly, well-controlled boosting, rather than suppression of systemic immunity, has been suggested as a new approach to modify disease pathology without directly targeting any of the brain's disease hallmarks. Here, we provide a short review of the mechanisms orchestrating the cross-talk between the brain and the immune system. We then discuss how immune checkpoint blockade directed against the PD-1/PD-L1 pathways could be developed as an immunotherapeutic approach to combat this disease using a regimen that will address the needs to combat AD.

Potential immunotherapy for Alzheimer disease and age-related dementia

2019 ◽  
Vol 21 (1) ◽  
pp. 21-25 ◽  
Keyword(s):  
Immune System ◽  
Alzheimer Disease ◽  
Cross Talk ◽  
Immune Checkpoint ◽  
Short Review ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
New Approach ◽  
Age Related ◽  
The Brain

Emerging results support the concept that Alzheimer disease (AD) and age-related dementia are affected by the ability of the immune system to contain the brain’s pathology. Accordingly, well-controlled boosting, rather than suppression of systemic immunity, has been suggested as a new approach to modify disease pathology without directly targeting any of the brain’s disease hallmarks. Here, we provide a short review of the mechanisms orchestrating the cross-talk between the brain and the immune system. We then discuss how immune checkpoint blockade directed against the PD-1/PD-L1 pathways could be developed as an immunotherapeutic approach to combat this disease using a regimen that will address the needs to combat AD.

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 Rethinking immune checkpoint blockade: ‘Beyond the T cell’

2021 ◽  
Vol 9 (1) ◽  
pp. e001460 ◽  
Author(s):  
Xiuting Liu ◽  
Graham D Hogg ◽  
David G DeNardo
Keyword(s):  
Immune System ◽  
T Cell ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Antitumor Immunity ◽  
Checkpoint Inhibitors ◽  
Clinical Success ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade

The clinical success of immune checkpoint inhibitors has highlighted the central role of the immune system in cancer control. Immune checkpoint inhibitors can reinvigorate anti-cancer immunity and are now the standard of care in a number of malignancies. However, research on immune checkpoint blockade has largely been framed with the central dogma that checkpoint therapies intrinsically target the T cell, triggering the tumoricidal potential of the adaptive immune system. Although T cells undoubtedly remain a critical piece of the story, mounting evidence, reviewed herein, indicates that much of the efficacy of checkpoint therapies may be attributable to the innate immune system. Emerging research suggests that T cell-directed checkpoint antibodies such as anti-programmed cell death protein-1 (PD-1) or programmed death-ligand-1 (PD-L1) can impact innate immunity by both direct and indirect pathways, which may ultimately shape clinical efficacy. However, the mechanisms and impacts of these activities have yet to be fully elucidated, and checkpoint therapies have potentially beneficial and detrimental effects on innate antitumor immunity. Further research into the role of innate subsets during checkpoint blockade may be critical for developing combination therapies to help overcome checkpoint resistance. The potential of checkpoint therapies to amplify innate antitumor immunity represents a promising new field that can be translated into innovative immunotherapies for patients fighting refractory malignancies.

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 &lt; 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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