CD40 Agonist Overcomes T Cell Exhaustion Induced by Chronic Myeloid Cell IL-27 Production in a Pancreatic Cancer Preclinical Model.
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ABSTRACT:
SUBMITTER: Burrack AL
PROVIDER: S-EPMC7977703 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:T-cell exhaustion is a phenomenon that represents the dysfunctional state of T cells in chronic infections and cancer and is closely associated with poor prognosis in many cancers. The endogenous T-cell immunity and genetically edited cell therapies (CAR-T) failed to prevent tumor immune evasion. The effector T-cell activity is perturbed by an imbalance between inhibitory and stimulatory signals causing a reprogramming in metabolism and the high levels of multiple inhibitory receptors like programmed cell death protein-1 (PD-1), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3), and Lymphocyte-activation gene 3 (Lag-3). Despite the efforts to neutralize inhibitory receptors by a single agent or combinatorial immune checkpoint inhibitors to boost effector function, PDAC remains unresponsive to these therapies, suggesting that multiple molecular mechanisms play a role in stimulating the exhaustion state of tumor-infiltrating T cells. Recent studies utilizing transcriptomics, mass cytometry, and epigenomics revealed a critical role of Thymocyte selection-associated high mobility group box protein (TOX) genes and TOX-associated pathways, driving T-cell exhaustion in chronic infection and cancer. Here, we will review recently defined molecular, genetic, and cellular factors that drive T-cell exhaustion in PDAC. We will also discuss the effects of available immune checkpoint inhibitors and the latest clinical trials targeting various molecular factors mediating T-cell exhaustion in PDAC.
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Project description:Irreversible T cell exhaustion limits the efficacy of programmed cell death 1 (PD-1) blockade. We observed that dual CD40-TLR4 stimulation within a single tumor restored PD-1 sensitivity and that this regimen triggered a systemic tumor-specific CD8+ T cell response. This approach effectively treated established tumors in diverse syngeneic cancer models, and the systemic effect was dependent on the injected tumor, indicating that treated tumors were converted into necessary components of this therapy. Strikingly, this approach was associated with the absence of exhausted PD-1hi T cells in treated and distant tumors, while sparing the intervening draining lymph node and spleen. Furthermore, patients with transcription changes like those induced by this therapy experienced improved progression-free survival with anti-PD-1 treatment. Dual CD40-TLR4 activation within a single tumor is thus an approach for overcoming resistance to PD-1 blockade that is unique in its ability to cause the loss of exhausted T cells within tumors while sparing nonmalignant tissues.
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Project description:Background and aims: Gut microbial metabolites and their host signaling pathways hold therapeutic potential for colorectal cancer (CRC). One example is short-chain fatty acids (SCFA), which are microbial metabolites generated from dietary fiber. This study aims to determine the pathogenesis of CRC from the host-microbiota perspective and the contributions of Ffar2, a SCFA receptor, to CRC. Methods: We have employed Apc-based models of CRC in conjunction with Ffar2 knock-out (ko) mice, Ffar2 conditional ko mice, and Ffar2 chemical agonism to reveal how a microbial metabolite receptor influences tumorigenesis in the colon. Utilizing human CRC datasets from The Cancer Genome Atlas aided our discovery of the links between Ffar2 function in dendritic cells and tumoral T cell dysfunction. Herein, we also used preclinical CRC models to test IL-27p28 neutralization or Ffar2 agonism as proof of concept for CRC prevention and treatment. Results: We have identified a mechanism by which Ffar2 deficiency potentiates tumorigenesis by affecting gut barrier integrity that increases tumor bacterial load and then altering IL-27+ dendritic cell populations and tumor CD8+ T cell phenotype and function. These events create a tumor immune milieu notable for dying and over-activated DCs and exhausted CD8+ T cells, which enables tumor growth. Proof-of-concept experiments in mice employing IL-27p28 neutralization or Ffar2 agonism reduced tumor burden. Conclusions: Our data support that loss of Ffar2 signaling potentiates tumorigenesis via a “two-hit” model, first by gut barrier breach and then by immune cell dysfunction. Our work supports that altering Ffar2 signaling or neutralizing IL-27 represent potential immunotherapy CRC treatment strategies.
2020-01-16 | GSE142691 | GEO
Project description:Agonistic anti-CD40 monoclonal antibody (mAb) therapy in combination with chemotherapy (chemoimmunotherapy) shows promise for the treatment of pancreatic ductal adenocarcinoma (PDA). To gain insight into immunological mechanisms of response and resistance to chemoimmunotherapy, we analyzed blood samples from patients (n = 22) with advanced PDA treated with an anti-CD40 mAb (CP-870,893) in combination with gemcitabine. We found a stereotyped cellular response to chemoimmunotherapy characterized by transient B cell, CD56+CD11c+HLA-DR+CD141+ cell, and monocyte depletion and CD4+ T cell activation. However, these cellular pharmacodynamics did not associate with outcomes. In contrast, we identified an inflammatory network in the peripheral blood consisting of neutrophils, cytokines (IL-6 and IL-8), and acute phase reactants (C-reactive protein and serum amyloid A) that was associated with outcomes. Furthermore, monocytes from patients with elevated plasma IL-6 and IL-8 showed distinct transcriptional profiles, including upregulation of CCR2 and GAS6, genes associated with regulation of leukocyte chemotaxis and response to inflammation. Patients with systemic inflammation, defined by neutrophil/lymphocyte ratio (NLR) greater than 3.1, had a shorter median overall survival (5.8 vs. 12.3 months) as compared with patients with NLR less than 3.1. Taken together, our findings identify systemic inflammation as a potential resistance mechanism to a CD40-based chemoimmunotherapy and suggest biomarkers for future studies.
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Project description:BackgroundA novel [64Cu]Cu-NOTA-aCD40 immunoPET tracer was developed to image a CD40+ pancreatic tumor model in C57BL/6 mice and to study the biodistribution profile of the agonist CD40 (aCD40) monoclonal antibody (mAb) alone or combined with other mAbs.ProceduresCopper-64 ([64Cu]Cu) labeled NOTA-aCD40 and NOTA-IgG (10 μg; 7 MBq) were injected intravenously into C57BL/6 mice with subcutaneous mT4 tumors to assess specificity 48 h post injection (p.i.) through positron emission tomography/computed tomography (PET/CT) imaging and biodistribution studies (n = 5). [64Cu]Cu-NOTA-aCD40 was injected alone or simultaneously in combination with a therapeutic mass of cold aCD40 (100 μg), aPD-1 (200 μg) and aCTLA-4 (200 μg) mAbs. A group of mice with or without tumor received the second round of injections 1 or 3 weeks apart, respectively. PET/CT imaging and biodistribution studies were performed at 48 h p.i. The organ dose for [64Cu]Cu was estimated based on biodistribution studies with 2 μg [64Cu]Cu-NOTA-aCD40 (corresponds to 5 mg patient dose) in non-tumor bearing mice.Results[64Cu]Cu-NOTA-aCD40 accumulation was 2.3- and 7.8-fold higher than [64Cu]Cu-NOTA-IgG in tumors and spleen, respectively, indicating the specificity of aCD40 mAb in a mouse pancreatic tumor model. Tumor accumulation of [64Cu]Cu-NOTA-aCD40 was 21.2 ± 7.3%ID/g at 48 h after injection. Co-injection of [64Cu]Cu-NOTA-aCD40 with cold aCD40 mAb alone or with PD-1 and CTLA-4 mAbs reduced both spleen and tumor uptake, whereas liver uptake was increased. With the second round of injections, the liver was the only organ with substantial uptake. With a 2 μg administered dose of [64Cu]Cu-NOTA-aCD40 in a dosimetry study, the liver to spleen ratio was greater compared to the 10 μg dose (2.8 vs 0.37; respectively). The human equivalent for the highest dose organ (liver) was 198 ± 28.7 μSv/MBq.ConclusionsA CD40-immunoreactive [64Cu]Cu-NOTA-aCD40 probe was developed. The ratio of spleen to liver accumulation exceeded that of the IgG isotype and was greatest with a single small, injected mass. The safety of human patient imaging with [64Cu]Cu was established based on extrapolation of the organ specificity to human imaging.
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