scholarly journals Sufficiency of CD40 activation and immune checkpoint blockade for T cell priming and tumor immunity

2020 ◽  
Vol 117 (14) ◽  
pp. 8022-8031 ◽  
Author(s):  
Alexander H. Morrison ◽  
Mark S. Diamond ◽  
Ceire A. Hay ◽  
Katelyn T. Byrne ◽  
Robert H. Vonderheide
Keyword(s):  
T Cell ◽  
Immune Checkpoint ◽  
Tumor Model ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Cell Responses ◽  
Adaptive Immune ◽  
Cd40 Activation ◽  
Polyfunctional T Cells ◽  
Complete Tumor

Innate immune receptors such as toll-like receptors (TLRs) provide critical molecular links between innate cells and adaptive immune responses. Here, we studied the CD40 pathway as an alternative bridge between dendritic cells (DCs) and adaptive immunity in cancer. Using an experimental design free of chemo- or radiotherapy, we found CD40 activation with agonistic antibodies (⍺CD40) produced complete tumor regressions in a therapy-resistant pancreas cancer model, but only when combined with immune checkpoint blockade (ICB). This effect, unachievable with ICB alone, was independent of TLR, STING, or IFNAR pathways. Mechanistically, αCD40/ICB primed durable T cell responses, and efficacy required DCs and host expression of CD40. Moreover, ICB drove optimal generation of polyfunctional T cells in this “cold” tumor model, instead of rescuing T cell exhaustion. Thus, immunostimulation via αCD40 is sufficient to synergize with ICB for priming. Clinically, combination αCD40/ICB may extend efficacy in patients with “cold” and checkpoint-refractory tumors.

scholarly journals Immune-checkpoint blockade of CTLA-4 (CD152) in antigen-specific human T-cell responses differs profoundly between neonates, children, and adults

2021 ◽  
Vol 10 (1) ◽  
pp. 1938475
Author(s):  
Aditya Arra ◽  
Maximilian Pech ◽  
Hang Fu ◽  
Holger Lingel ◽  
Franziska Braun ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Checkpoint ◽  
T Cell Responses ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Cell Responses ◽  
Human T Cell

scholarly journals Bifunctional PD-1 × αCD3 × αCD33 fusion protein reverses adaptive immune escape in acute myeloid leukemia

Blood ◽  
2018 ◽  
Vol 132 (23) ◽  
pp. 2484-2494 ◽  
Author(s):  
Monika Herrmann ◽  
Christina Krupka ◽  
Katrin Deiser ◽  
Bettina Brauchle ◽  
Anetta Marcinek ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
T Cell ◽  
T Cell Activation ◽  
Immune Checkpoint ◽  
Myeloid Leukemia ◽  
Cell Activation ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Adaptive Immune ◽  
Acute Myeloid

Abstract The CD33-targeting bispecific T-cell engager (BiTE) AMG 330 proved to be highly efficient in mediating cytolysis of acute myeloid leukemia (AML) cells in vitro and in mouse models. Yet, T-cell activation is correlated with upregulation of programmed cell death-ligand 1 (PD-L1) and other inhibitory checkpoints on AML cells that confer adaptive immune resistance. PD-1 and PD-L1 blocking agents may counteract T-cell dysfunction, however, at the expense of broadly distributed immune-related adverse events (irAEs). We developed a bifunctional checkpoint inhibitory T cell–engaging (CiTE) antibody that combines T-cell redirection to CD33 on AML cells with locally restricted immune checkpoint blockade. This is accomplished by fusing the extracellular domain of PD-1 (PD-1ex), which naturally holds a low affinity to PD-L1, to an αCD3.αCD33 BiTE-like scaffold. By a synergistic effect of checkpoint blockade and avidity-dependent binding, the PD-1ex attachment increases T-cell activation (3.3-fold elevation of interferon-γ) and leads to efficient and highly selective cytotoxicity against CD33+PD-L1+ cell lines (50% effective concentration = 2.3-26.9 pM) as well as patient-derived AML cells (n = 8). In a murine xenograft model, the CiTE induces complete AML eradication without initial signs of irAEs as measured by body weight loss. We conclude that our molecule preferentially targets AML cells, whereas high-affinity blockers, such as clinically approved anticancer agents, also address PD-L1+ non-AML cells. By combining the high efficacy of T-cell engagers with immune checkpoint blockade in a single molecule, we expect to minimize irAEs associated with the systemic application of immune checkpoint inhibitors and suggest high therapeutic potential, particularly for patients with relapsed/ refractory AML.

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.

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 700 Increasing MHC-I expression to potentiate immune checkpoint blockade therapy

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A728-A728
Author(s):  
Shengqing Gu ◽  
Wubing Zhang ◽  
Xiaoqing Wang ◽  
Peng Jiang ◽  
Nicole Traugh ◽  
...  
Keyword(s):  
T Cell ◽  
Cancer Cells ◽  
Cancer Patients ◽  
Immune Checkpoint ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Mhc I ◽  
Expression Signature ◽  
Smac Mimetics ◽  
Smac Mimetic

BackgroundCancer immunotherapy, especially immune checkpoint blockade (ICB) therapy, is leading to a paradigm shift in cancer treatment, as a small percentage of cancer patients have obtained durable remission following ICB treatment. Successful ICB responses rely on cancer cells presenting antigens to the cell surface via the major histocompatibility complex (MHC), which activates antigen-specific T-lymphocytes to kill cancer cells. Type-I MHC (MHC-I) is wildly expressed in all cell types and mediates the interaction with cytotoxic CD8 T cells. However, over 65% of cancer patients are estimated to show defects in MHC-I-mediated antigen presentation, including downregulation of its expression that can lead to primary or acquired resistance to ICB therapy, and therapeutic strategies to effectively restore or boost MHC-I are limited.MethodsHere, we employed a CRISPR screening approach with dual-marker FACS sorting to identify factors that decouple the regulation of MHC-I and PD-L1. The experimentally validated target was used to generate a KO differential expression signature. Using this signature, we analyzed transcriptome data from drug perturbation studies to identify drugs that regulate MHC-I but not PD-L1. Finally, we validated the effect of the identified drug to enhance ICB response in a T-cell-dependent manner in vivo.ResultsCRISPR screens identified TRAF3, a suppressor of the NF-κB pathway, as a negative regulator of MHC-I but not PD-L1. The Traf3-knockout (Traf3-KO) gene expression signature is associated with better survival in ICB-naive cancer patients and better ICB response. We then screened for drugs with similar transcriptional effects as this signature and identified SMAC mimetics. We experimentally validated that the SMAC mimetic birinapant upregulates MHC-I, sensitizes cancer cells to T-cell-dependent killing, and adds to ICB efficacy. However, in cancer cells with high NF-κB activity, the effect of birinapant on MHC-I is weak, indicating context-dependent MHC-I regulation.ConclusionsIn summary, Traf3 deletion specifically upregulates MHC-I without inducing PD-L1 in response to various cytokines and sensitizes cancer cells to T-cell-driven cytotoxicity. The SMAC mimetic birinapant phenocopies Traf3-knockout and sensitizes MHC-I-low melanoma to ICB therapy. Further studies are needed to elucidate the context-dependencies of MHC-I regulation. Our findings provide preclinical rationale for treating some tumors expressing low MHC-I with SMAC mimetics to enhance sensitivity to immunotherapy. The approach used in this study can be generalized to identify other drugs that enhance immunotherapy efficacy.AcknowledgementsThis study was supported by grants from the NIH (R01CA234018 to XSL, R01AI137337 to BEG, P50CA101942-12 and P50CA206963 to GJF), Breast Cancer Research Foundation (BCRF-19-100 to XSL), Burroughs Wellcome Career Award in Medical Sciences (to BEG), and Sara Elizabeth O'Brien Trust Fellowship (to SG).We thank Drs. Kai Wucherpfennig and Deng Pan for their insightful suggestions on this study.Ethics ApprovalAll mice were housed in standard cage in Dana-Farber Cancer Institute Animal Resources Facility (ARF). All animal procedures were carried out under the ARF Institutional Animal Care and Use Committee (IACUC) protocol and were in accordance with the IACUC standards for the welfare of animals.

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