scholarly journals Altered interactions between circulating and tissue-resident CD8 T cells with the colonic mucosa define colitis associated with immune checkpoint inhibitors

2021 ◽  
Author(s):  
Molly Thomas ◽  
Kamil Slowikowski ◽  
Kasidet Manakongtreecheep ◽  
Pritha Sen ◽  
Jessica Tantivit ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Intestinal Barrier Function ◽  
Cell Populations ◽  
Communication Analysis

Therapeutic blockade of co-inhibitory immune receptors PD-1 and CTLA-4 has revolutionized oncology, but treatments are limited by immune-related adverse events (IRAEs). IRAE Colitis (irColitis) is the most common, severe IRAE affecting up to 25% of patients on dual PD-1 and CTLA-4 inhibition. Here, we present a systems biology approach to define the cell populations and transcriptional programs driving irColitis. We collected paired colon mucosal biopsy and blood specimens from 13 patients with irColitis, 8 healthy individuals, and 8 controls on immune checkpoint inhibitors (ICIs), and analyzed them with single-cell/nuclei RNA sequencing with paired TCR and BCR sequencing, multispectral fluorescence microscopy, and secreted factor analysis (Luminex). We profiled 299,407 cells from tissue and blood and identified 105 cell subsets that revealed significant tissue remodeling in active disease. Colon mucosal immune populations were dominated by tissue-resident memory (Trm) ITGAE-expressing CD8 T cells representing a phenotypic spectrum defined by gene programs associated with T cell activation, cytotoxicity, cycling, and exhaustion. CD8 Trm and effector CD4 T cells upregulated type 17 immune programs (IL17A, IL26) and Tfh-like programs (CXCL13, PDCD1). We also identified for the first time an increased abundance of two KLRG1 and ITGB2-expressing CD8 T cell populations with circulatory cell markers, including a GZMK Trm-like population and a CX3CR1 population that is predicted to be intravascular. These two populations were more abundant in irColitis patients treated with dual PD-1/CTLA-4 inhibition than those receiving anti-PD-1 monotherapy. They also had significant TCR sharing with PBMCs, suggesting a circulatory origin. In irColitis we observed significant epithelial turnover marked by fewer LGR5-expressing stem cells, more transit amplifying cells, and upregulation of apoptotic and DNA-sensing programs such as the cGAS-STING pathway. Mature epithelial cells with top crypt genes upregulated interferon-stimulated pathways, CD274 (PD-L1), anti-microbial genes, and MHC-class II genes, and downregulated aquaporin and solute-carrier gene families, likely contributing to epithelial cell damage and absorptive dysfunction. Mesenchymal remodeling was defined by increased endothelial cells, both in irColitis patients and specifically in patients on dual PD-1/CTLA-4 blockade. Cell-cell communication analysis identified putative receptor-ligand pairs that recruit CD8 T cells from blood to inflamed endothelium and positive feedback loops such as the CXCR3 chemokine system that retain cells in tissue. This study highlights the cellular and molecular drivers underlying irColitis and provides new insights into the role of CTLA-4 and PD-1 signaling in maintaining CD8 Trm homeostasis, regulating CD8 T recruitment from blood, and promoting epithelial-immune crosstalk critical to gastrointestinal immune tolerance and intestinal barrier function.

scholarly journals 643 Vasoactive intestinal peptide as a novel immune checkpoint molecule in activated T cells

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A672-A672
Author(s):  
Sruthi Ravindranathan ◽  
Tenzin Passang Fnu ◽  
Edmund Waller
Keyword(s):  
T Cells ◽  
T Cell ◽  
Vasoactive Intestinal Peptide ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Immune Checkpoint ◽  
Cd4 T Cells ◽  
Cell Activation ◽  
Checkpoint Inhibitors ◽  
Activated T Cells

BackgroundOnly a fraction of cancer patients responds to current antibody-based immune checkpoint inhibitors.1 Our lab has identified vasoactive intestinal peptide-receptor (VIP-R) signaling as a targetable immune checkpoint pathway in cancer. VIP is a small neuropeptide with known immunosuppressive effects on T cells, in particular, CD4+ T cells.2–5 However, little is known about VIP-R signaling in CD8+ T cells. To define mechanisms by which VIP limits T cell activation and function, we studied the regulation of VIP and VIP receptors (VIP-R) in T cells following their activation in vitro and in mouse models of cancer.MethodsT cells from healthy human donors and murine splenocytes were activated using anti-CD3 coated plates. Western blots measured intracellular pre-pro-VIP, along with its cognate receptors; VPAC1 and VPAC2. Purified cultures of CD4+ and CD8+ T cells were used to interrogate the protein expression on specific T cell subsets. Activation and chemokine receptor expression was assessed by flow cytometry to evaluate T cell response to VIP-R antagonists in vitro and in tumor-bearing mice engrafted with pancreatic cancer cell lines.ResultsBoth murine and human T cells upregulate pre-pro-VIP following TCR stimulation with similar kinetics of VIP receptors between species. VIP expression is upregulated in vivo following treatment of tumor-bearing mice with anti-PD1 MoAb. VIP expression is temporally correlated with the upregulation of other co-inhibitory molecules. VPAC1 expression modestly increased in activated T cells while VPAC2 expression decreased. A non-canonical high molecular weight (HMW) form of VPAC2-related protein robustly and transiently increase in activated T cells. Expression of HMW form of VPAC2 is only detected in activated CD4+ T cells. Of note, activated CD4+ but not CD8+ T cells upregulate pre-pro-VIP. Pharmacological inhibition of VIP-R signaling significantly increased CD69+, OX40+, Lag3+, and PD1+ expression in CD4+ subsets compared to activated T cells without VIP-R antagonists (p < 0.05). In contrast, CD8+ T cells upregulate VPAC1 but not VPAC2 receptor following activation. VIP-R antagonist treatment of activated CD8+ T cells significantly decreased CXCR4+ expression (p < 0.05). CXCR3 and CXCR5 expression were not affected by VIP-R antagonist treatment.ConclusionsVIP-R signaling is a novel immune autocrine and paracrine checkpoint pathway in activated CD4+ T cells. Activated CD4+ and CD8+ T cells demonstrate different kinetics of VPAC1 and VPAC2 expression, suggesting different immune-regulatory responses to VIP-R antagonists. Understanding VIP-R signaling induced during T cell activation can lead to specific drugs that target VIP-R pathways to enhance cancer immunotherapy.AcknowledgementsWe thank healthy volunteers for blood samples. The authors also thank the shared resources at Emory University, namely, Emory Flow Cytometry Core (EFCC) and Integrated Cellular Imaging Core (ICI) and Yerkes Nonhuman Primate Genomics Core that provided services or instruments at subsidized cost to conduct some of the reported experiments. This work was supported in part by Katz Foundation funding, Georgia Research Alliance, and Emory School of Medicine Dean's Imagine, Innovate and Impact (I3) venture award to Edmund K. Waller.ReferencesDarvin P, Toor SM, Sasidharan Nair V, Elkord E. Immune checkpoint inhibitors: recent progress and potential biomarkers. Experimental and Molecular Medicine 2018.Wang HY, Jiang XM, Ganea D. The Neuropeptides VIP and PACAP Inhibit IL-2 Transcription by Decreasing c-Jun and Increasing JunB Expression in T Cells. J Neuroimmunol 2000;104(1):68–78.Delgado M. Vasoactive intestinal peptide generates CD4+CD25+ regulatory T Cells in Vivo. J Leukoc Biol 2005.Anderson P, Gonzalez-Rey E. Vasoactive intestinal peptide induces cell cycle arrest and regulatory functions in human T cells at multiple levels. Mol Cell Biol 2010.Delgado M, Ganea D. Vasoactive intestinal peptide: a neuropeptide with pleiotropic immune functions. Amino Acids. NIH Public Access July 2013, 25–39.Ethics ApprovalDe-identified blood samples from consented healthy volunteers (IRB 00046063) were obtained with approval from Institutional Review Boards.

scholarly journals 781 Validation of the combinatorial effect of blinatumomab and nivolumab in cancer therapy

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A831-A831
Author(s):  
Tienan Wang ◽  
Qing Lin ◽  
Jie Zhang
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Immune Checkpoint ◽  
Culture System ◽  
Cell Activation ◽  
Checkpoint Inhibitors

BackgroundCancer immunotherapies, including immune checkpoint inhibitors, CAR-T, cancer vaccines and bispecific antibodies, have been brought to spot light in recent years as several therapeutic strategies targeting the immune system have produced exciting clinical results. Bispecific antibody typically play dual roles in blocking the immune checkpoint and redirecting/re-boosting the function of the immune effector cells. Blinatumomab belongs to CD3 bispecific T cell engager (CD3 BiTE), which was engineered to harbor two arms binding with CD3 and CD19 simultaneously and direct CD8+ T cells to specifically recognize CD19 positive lymphoma cells to execute cytotoxicity. Approval of Blinatumomab for patients with relapse/refractory B cell acute lymphoblastic leukemia (ALL) has driven remarkable increase in combination studies of Blinatumomab with other immunotherapies such as checkpoint inhibitors.MethodsIn this study, we developed CD8+ T cytotoxic system targeting different B lymphoma cell line and fully validated the function of Blinatumomab in promoting target tumor cell lysis by primary CD8+ T cells (figure 1). In addition, we established a mixed lymphocyte and tumor system to mimic physiological TME to dissect the combinational role of Nivolumab and Blinatumomab (figure 2).ResultsThe result suggest that combinatory therapy is highly depend on the dosage of Blinatumomab and also T cell number in the TME, which might give an instruction for ongoing clinical trial design. Finally, we have employed humanized mouse models bearing Raji or Daudi tumor cells to further validate this combination treatment in vivo. Both In-vivo and In-vitro data support that Blinatumomab is dominant in activing T cell and Nivolumab can only exhibit synergistic effect under suboptimal dosage of Blinatumomab.Abstract 781 Figure 1Establishment of In vitro co-culture system for CD3 BiTEestablish in vitro human PBMC based system to validate CD3 BiTE functionAbstract 781 Figure 2Opdivo and CD3 BiTE CombinationOpdivo could further promote T cell activation under the treatment of CD3 BiTEConclusionsSuccessfully establish in vitro system to evaluate the function of CD3 BiTE and also take advantage of MLR/tumor co-culture system to demonstrate PD1 antibody could further promote T cell activation under appropriate dosage of CD3 BiTE.

scholarly journals Inhibition of the PI3K/mTOR Pathway in Breast Cancer to Enhance Response to Immune Checkpoint Inhibitors in Breast Cancer

2021 ◽  
Vol 22 (10) ◽  
pp. 5207
Author(s):  
Chi Yan ◽  
Jinming Yang ◽  
Nabil Saleh ◽  
Sheau-Chiann Chen ◽  
Gregory D. Ayers ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
Tumor Growth ◽  
Cd8 T Cells ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Mtor Pathway ◽  
Complete Regression ◽  
Mtor Inhibition

Objectives: Inhibition of the PI3K/mTOR pathway suppresses breast cancer (BC) growth, enhances anti-tumor immune responses, and works synergistically with immune checkpoint inhibitors (ICI). The objective here was to identify a subclass of PI3K inhibitors that, when combined with paclitaxel, is effective in enhancing response to ICI. Methods: C57BL/6 mice were orthotopically implanted with syngeneic luminal/triple-negative-like PyMT cells exhibiting high endogenous PI3K activity. Tumor growth in response to treatment with anti-PD-1 + anti-CTLA-4 (ICI), paclitaxel (PTX), and either the PI3Kα-specific inhibitor alpelisib, the pan-PI3K inhibitor copanlisib, or the broad spectrum PI3K/mTOR inhibitor gedatolisib was evaluated in reference to monotherapy or combinations of these therapies. Effects of these therapeutics on intratumoral immune populations were determined by multicolor FACS. Results: Treatment with alpelisib + PTX inhibited PyMT tumor growth and increased tumor-infiltrating granulocytes but did not significantly affect the number of tumor-infiltrating CD8+ T cells and did not synergize with ICI. Copanlisib + PTX + ICI significantly inhibited PyMT growth and increased activation of intratumoral CD8+ T cells as compared to ICI alone, yet did not inhibit tumor growth more than ICI alone. In contrast, gedatolisib + ICI resulted in significantly greater inhibition of tumor growth compared to ICI alone and induced durable dendritic-cell, CD8+ T-cell, and NK-cell responses. Adding PTX to this regimen yielded complete regression in 60% of tumors. Conclusion: PI3K/mTOR inhibition plus PTX heightens response to ICI and may provide a viable therapeutic approach for treatment of metastatic BC.

scholarly journals 540 Baseline mTOR transcriptional signatures in CD8 T cells are associated with immune-related adverse events but not anti-tumor responses in patients receiving immune checkpoint inhibitors

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A570-A570
Author(s):  
Chen Zhao ◽  
Matthew Mule ◽  
Andrew Martins ◽  
Iago Pinal Fernandez ◽  
Renee Donahue ◽  
...  
Keyword(s):  
T Cells ◽  
Adverse Events ◽  
Tumor Immunity ◽  
Cd8 T Cells ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Effector Memory ◽  
Link Type ◽  
Anti Tumor Activity

BackgroundImmune checkpoint inhibitors (ICIs) have changed the cancer treatment landscape, but immune-related adverse events (irAEs) can affect a wide range of tissues in patients receiving ICIs. Severe irAEs can be life-threatening or fatal and prohibit patients from receiving further ICI treatment. While the clinical features of irAEs are well documented, the pathological mechanisms and predictive biomarkers are largely unknown. In addition, there is a critical need to preserve ICI-induced anti-tumor immunity while controlling for irAEs, which requires deciphering molecular and cellular signatures associated specifically with irAEs beyond those more generally linked to anti-tumor immunity.MethodsTo unbiasedly identify immune cells and states associated with irAEs, we applied CITE-seq to measure transcripts and surface proteins (83 protein markers) from PBMCs collected from patients with thymic epithelial tumors before and after treatment with an anti-PD-L1 antibody (avelumab, NCT01772004, NCT03076554).ResultsSamples from 9 patients were analyzed. No patient had a history of pre-existing paraneoplastic autoimmune disease. Anti-tumor activity was observed in all cases, and 5 patients had clinical and/or biochemical evidence of immune-related muscle inflammation (myositis with or without myocarditis). Multilevel models applied within highly resolved cell clusters revealed transcriptional states associated with ICI response and more uniquely with irAEs. A total of 190,000 cells were included in the analysis after quality control. Most notably, CD45RA+ effector memory CD8 T cells with an mTOR transcriptional signature were highly enriched at baseline and post treatment in patients with irAEs.ConclusionsOur findings suggest the potential therapeutic avenues by using mTOR inhibitors to dampen autoimmune responses while potentially sparing anti-tumor activity, to prevent treatment discontinuation and improve clinical outcomes for cancer patients treated with ICIs.AcknowledgementsThis research was supported in part by the Intramural Research Program of the NCI (the Center for Cancer Research), NIAID and NIAMS, and through a Cooperative Research and Development Agreement between the National Cancer Institute and EMD Serono.Trial RegistrationNCT01772004, NCT03076554Ethics ApprovalThis study is approved by NCI institutional review board.

scholarly journals Review of Indications of FDA-Approved Immune Checkpoint Inhibitors per NCCN Guidelines with the Level of Evidence

Cancers ◽  
2020 ◽  
Vol 12 (3) ◽  
pp. 738 ◽  
Author(s):  
Raju K. Vaddepally ◽  
Prakash Kharel ◽  
Ramesh Pandey ◽  
Rohan Garje ◽  
Abhinav B. Chandra
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Molecular Mechanisms ◽  
Checkpoint Inhibitors ◽  
Hematopoietic Cells ◽  
Fda Approval ◽  
Programmed Death ◽  
Cancerous Cells

Cancer is associated with higher morbidity and mortality and is the second leading cause of death in the US. Further, in some nations, cancer has overtaken heart disease as the leading cause of mortality. Identification of molecular mechanisms by which cancerous cells evade T cell-mediated cytotoxic damage has led to the modern era of immunotherapy in cancer treatment. Agents that release these immune brakes have shown activity to recover dysfunctional T cells and regress various cancer. Both cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and Programmed Death-1 (PD-1) play their role as physiologic brakes on unrestrained cytotoxic T effector function. CTLA-4 (CD 152) is a B7/CD28 family; it mediates immunosuppression by indirectly diminishing signaling through the co-stimulatory receptor CD28. Ipilimumab is the first and only FDA-approved CTLA-4 inhibitor; PD-1 is an inhibitory transmembrane protein expressed on T cells, B cells, Natural Killer cells (NKs), and Myeloid-Derived Suppressor Cells (MDSCs). Programmed Death-Ligand 1 (PD-L1) is expressed on the surface of multiple tissue types, including many tumor cells and hematopoietic cells. PD-L2 is more restricted to hematopoietic cells. Blockade of the PD-1 /PDL-1 pathway can enhance anti-tumor T cell reactivity and promotes immune control over the cancerous cells. Since the FDA approval of ipilimumab (human IgG1 k anti-CTLA-4 monoclonal antibody) in 2011, six more immune checkpoint inhibitors (ICIs) have been approved for cancer therapy. PD-1 inhibitors nivolumab, pembrolizumab, cemiplimab and PD-L1 inhibitors atezolizumab, avelumab, and durvalumab are in the current list of the approved agents in addition to ipilimumab. In this review paper, we discuss the role of each immune checkpoint inhibitor (ICI), the landmark trials which led to their FDA approval, and the strength of the evidence per National Comprehensive Cancer Network (NCCN), which is broadly utilized by medical oncologists and hematologists in their daily practice.

scholarly journals Alpha Thalassemia/Intellectual Disability X-Linked Deficiency Sensitizes Non-Small Cell Lung Cancer to Immune Checkpoint Inhibitors

2020 ◽  
Vol 10 ◽  
Author(s):  
Tao Hou ◽  
Shun Jiang ◽  
Yapeng Wang ◽  
Yangchun Xie ◽  
Haixia Zhang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
T Cells ◽  
T Cell ◽  
Small Cell Lung Cancer ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Tumor Volume ◽  
Checkpoint Inhibitors ◽  
Small Cell ◽  
Small Cell Lung

BackgroundThe immune checkpoint inhibitors (ICIs) have achieved great success in the treatment of non-small cell lung cancer (NSCLC) patients. However, the response rate is low. The molecular mechanism involved in the effectiveness of ICIs remains to be elucidated.MethodsATRX mutation incidence among human cancers was analyzed from TCGA database. Atrx-deficient Lewis lung cancer cell line (LLC-sgAtrx) was established via AAV-CRISPR. Subcutaneous and metastasis models were established by subcutaneous and intravenous injection of LLC-sgAtrx and LLC-sgNTC cells into female C57BL/6 mice. The mice were treated with anti-PD1, anti-CLTA4 or Rat IgG2a. Tumor volume was determined by Vernier calipers and the IVIS imaging system. The proportions of CD3+ T cells, CD45+ immune cells, and the expression of pMHC I and PDL1 were determined by flow cytometry. The T cell cytotoxicity was determined by co-culture experiment.ResultsTCGA data showed that Atrx is a tumor suppressor mutated at high frequency among various human cancers. The tumor volume of mice bearing LLC-sgAtrx was significantly shrinked and the median survival of mice was significantly longer after anti-PD1 and anti-CTLA4 treatment. Flowcytometry results showed that Atrx deficiency increase the penetration of CD3+ T cell into the tumor microenvironment and enhanced antigen presentation after IFNγ stimulation. Additionally, the tumor cells with Atrx deficiency were more easily to be damaged by T cells under IFNγ stimulation.ConclusionThe present study demonstrated that Atrx deficiency sensitize lung cancer cells to ICIs by multiple mechanisms. And ATRX may serve as a promising biomarker for ICIs which helps patient stratification and decision making.

646 Evaluating a preclinical model of contact hypersensitivity for skin immune checkpoint toxicity

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A683-A683
Author(s):  
Barbara Ma ◽  
Abhinav Jaiswal ◽  
K Sanjana Devi ◽  
Qingrong Huang ◽  
Joy Hsu ◽  
...  
Keyword(s):  
T Cells ◽  
Adverse Events ◽  
Clin Oncol ◽  
Cd8 T Cells ◽  
Murine Model ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Immune Checkpoint Blockade ◽  
Contact Hypersensitivity

BackgroundImmune checkpoint inhibitors (ICIs) are limited by the high incidence of immune-related adverse events (irAEs) occurring in up to 40% of solid tumor patients on anti-PD-1 monotherapy 1 2 and 72% in anti-CTLA-4/anti-PD-1 combination.3 4 These toxicities can cause treatment cessation, hospitalization and even death.5–7 IrAEs are variable in severity, timing, onset, and remain poorly understood. Amongst the different toxicities, skin irAEs are most frequent, occur the earliest, and are correlated with a positive prognosis.4 8 However, there is a lack of preclinical models to study checkpoint toxicity. We evaluated a murine model of allergic contact dermatitis (contact hypersensitivity to 2,4-dinitrofluorobenzene) that is mediated by CD8+ T cells to gain a mechanistic understanding of skin checkpoint toxicity.MethodsC57BL/6 mice (n = 5 per group) were sensitized epicutaneously on shaved flank with hapten 0.5% DNFB on day -5 and elicited on their ears with DNFB on day 0. Starting four weeks later, mice were treated with either anti-programmed cell death protein (PD-1) or isotype. At the time of the first recall challenge only, mice were given either anti-PD-1 or isotype. Mice received subsequent rechallenges with DNFB to the ears and ear swelling was measured at various time points. Mice were depleted of circulating or skin CD8+ T cells by anti-CD8 mAbs from day 29 onwards, and maintained weekly, as in this model CD8+ T cells are the main hapten responder population. Samples were collected for histochemistry and analyzed by flow cytometry.ResultsOur data indicate that despite the depletion of circulating T cells, anti-PD-1 recipients mount a higher initial recall response to contact agents. Higher ear swelling was observed with increased inflammation in these mice. Our data suggest anti-PD-1 can liberate local T cell responses in the absence of a contribution from blood, and may offer a model to test therapeutic interventions to alleviate peripheral immune toxicities.ConclusionsOur results suggest that this murine model of contact hypersensitivity represents a potential model for skin immune checkpoint toxicities. This model of locally-mediated inflammatory recall may advance the goal of uncoupling toxicity from efficacy in patients with immune-related adverse events.Ethics ApprovalThe animal study was approved by Weill Cornell Medicine’s IACUC; approval number D16-00186.ReferencesNaidoo J, Page DB, Li BT, et al. Toxicities of the anti-PD-1 and anti-PD-L1 immune checkpoint antibodies. Ann Oncol 2015;26(12):2375–91. doi: 10.1093/annonc/mdv383.Belum VR, Benhuri B, Postow MA, et al. Characterisation and management of dermatologic adverse events to agents targeting the PD-1 receptor. Eur J Cancer 2016;60:12–25. doi: 10.1016/j.ejca.2016.02.010.Postow MA, Sidlow R, Hellmann MD. Immune-Related Adverse Events Associated with Immune Checkpoint Blockade. N Engl J Med 2018;378(2):158–168. doi: 10.1056/NEJMra1703481.Martins F, Sofiya L, Sykiotis GP, et al. Adverse effects of immune-checkpoint inhibitors: epidemiology, management and surveillance. Nat Rev Clin Oncol 2019;16(9):563–580. doi: 10.1038/s41571-019-0218-0.Puzanov I, Diab A, Abdallah K, et al. Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the society for immunotherapy of cancer (SITC) Toxicity Management Working Group. J Immunother Cancer 2017;5(1):95. doi: 10.1186/s40425-017-0300-z.Wills B, Brahmer JR, Naidoo J. Treatment of complications from immune checkpoint inhibition in patients with lung cancer. Curr Treat Options Oncol 2018;19(9):46. doi: 10.1007/s11864-018-0562-9.Michot JM, Bigenwald C, Champiat S, et al. Immune-related adverse events with immune checkpoint blockade: a comprehensive review. Eur J Cancer 2016;54:139–148. doi: 10.1016/j.ejca.2015.11.016.Phillips GS, Wu J, Hellmann MD, et al. Treatment outcomes of immune-related cutaneous adverse events. J Clin Oncol 2019:JCO1802141. doi: 10.1200/JCO.18.02141.

859 Inhibition of the kinase activity of hematopoietic progenitor kinase 1 enhances anti-PD-1-induced reinvigoration of human tumor-infiltrating CD8+ T cells

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A912-A912
Author(s):  
Yongjoon Lee ◽  
Seung Hyuck Jeon ◽  
A Yeong Park ◽  
Suyeon Jo ◽  
Jinhwa Lee ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Immune Checkpoint ◽  
Kinase Activity ◽  
Checkpoint Inhibitors ◽  
Ex Vivo ◽  
Human Tumor ◽  
Hematopoietic Progenitor ◽  
Effector Functions

BackgroundImmune checkpoint inhibitors (ICIs) including anti-CTLA-4, anti-PD-1, and anti-PD-L1 have been clinically used for the treatment of various types of cancer. However, ICIs have a limited efficacy, and it is required to develop a strategy to enhance the efficacy of ICIs. Hematopoietic progenitor kinase 1 (HPK1) was recently known to inhibit T cell receptor (TCR) signaling by targeting SLP76 thus suppress T-cell effector functions.MethodsIn the present study, we examined the expression of HPK-1 and SLP76 in tumor-infiltrating lymphocytes (TILs) obtained from renal cell carcinoma tissues, in relation with the expression of PD-1 and other immune checkpoint receptors by performing flow cytometry analysis. In addition, we examined if inhibition of the kinase activity of HPK1 by CMPD0914, that is a potent, selective and orally available HPK1 inhibitor, enhanced effector functions of tumor-infiltrating CD8+ T cells in the presence of anti-PD-1 blocking antibodies.ResultsFirst, we found that HPK1 and SLP76 are expressed in both CD8+ and CD4+ T cells including Foxp3+ regulatory T cells irrespective of PD-1 expression. Intriguingly, the expression levels of HPK1 and SLP76 were significantly higher in the PD-1bright population compared to the PD-1- or PD-1dim populations. Further characterization revealed that HPK1 and SLP76 were highly expressed in CD8+ T-cell populations expressing TOX, a transcription regulator of T-cell exhaustion, or TCF-1, a transcription factor related to progenitor-like exhausted T cells. In ex vivo functional assays, anti-PD-1 treatment increased the production of IFN-γ and TNF, and the expression of a proliferation marker, Ki-67 among tumor-infiltrating CD8+ T cells. Interestingly, the effects of anti-PD-1 treatment were further enhanced by the combination treatment with CMPD0914.ConclusionsIn summary, we demonstrated that HPK1 and SLP76 are expressed by human tumor-infiltrating T cells, particularly PD-1brightCD8+ T cells, and that anti-PD-1-induced T-cell reinvigoration is significantly enhanced by an HPK1 inhibitor, CMPD0914, rationalizing the combination of anti-PD1/PD-L1 and HPK1 inhibitors for the treatment of cancer.

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