Predictive biomarkers for response to nivolumab in head and neck squamous cell carcinoma (HNSCC) (NCT#03652142).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 6060-6060
Author(s):  
Amanda Psyrri ◽  
Niki Gavrielatou ◽  
Aris Spathis ◽  
Maria Anastasiou ◽  
Ekaterina Fortis ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Checkpoint Inhibitors ◽  
Predictive Biomarkers ◽  
Cd8 T Cell ◽  
Post Treatment ◽  
Tertiary Lymphoid Structures ◽  
Pre Treatment ◽  
Lymphoid Structures

6060 Background: Tumor immune cell compositions determine response to immunotherapy. For a better understanding of the mechanisms of resistance to nivolumab in HNSCC, we sought to investigate a prospective cohort of longitudinal HNSCC samples from recurrent/metastatic HNSCC pts treated with nivolumab and identify biomarkers of response and resistance. We will specifically focus on modulation of immune markers following two cycles of nivolumab. Methods: Patients with platinum-refractory HNSCC with no contraindication to nivolumab therapy are included in this study. Tumor biopsies are performed at baseline, 24-72 hours after the second cycle and at progression with appropriate written informed consent. Samples were assessed for the presence of Tertiary Lymphoid Structures (TLS), PD-L1 expression (TPS and CPS) and CD8 T cell infiltrates combined with Ki67 (CD8/Ki67 double IHC stain). The primary outcome measure of the study is change in the percentage of immune cells in post treatment compared to baseline biopsies. Secondary endpoints include safety of performing a second biopsy, best overall response rate, biomarker expression in association with response and survival. Evaluation of other biomarkers including tumor mutational burden, HLA class I and II expression and adaptive immunity cell populations using multiplex IF is ongoing. Results: Of 20 patients evaluable for response, 14 had PD (8 of whom showed hyper-progression) and 6 attained disease control (1 with PR). PD-L1 status (CPS or TPS) was not altered by treatment (p = 0.905) and CPS > 20 pre-treatment showed a favorable trend towards response (p = 0.117). Absence of tertiary lymphoid structures was associated with disease progression (p = 0.0374). Infiltrating plasma cell count remained unchanged pre- and post-treatment and was unrelated to response (p = 0.458). The percentage of proliferating CD8+ T cells (CD8+/Ki67+) increased in post-treatment biopsies in the entire population (p = 0.022) and especially in progressors (p = 0.039). Pre-treatment CD8+ T cell density was higher in patients with hyper-progression compared to progressors (p = 0.029). Conclusions: Increased percentage of proliferating CD8+ T cells in progressors might represent dysfunctional T cells as has been recently shown in melanoma pts (Li H et al Cell 2019) and clinical efforts to reactivate intratumoral T cells may augment the efficacy of PD1 checkpoint inhibitors. Clinical trial information: NCT03652142.

Interrogation of neoantigen-specific CD8 T cells in peripheral blood following PD-L1 blockade in patients with metastatic urothelial carcinoma (mUC).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3075-3075
Author(s):  
Jeppe Sejerø Holm ◽  
Samuel Aaron Funt ◽  
Anne-Mette Bjerregaard ◽  
James L. Reading ◽  
Colleen Anne Maher ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cell Response ◽  
Treatment Initiation ◽  
Cd8 T Cell ◽  
T Cell Response ◽  
Post Treatment ◽  
Cell Responses ◽  
Pre Treatment

3075 Background: Proliferation of CD8 T cells can be detected in the blood of cancer patients (pts) following a single dose of immune checkpoint blockade (ICB) and tends to be more robust in responding pts. Furthermore, tumor mutational burden (TMB) is seen to predict outcome to ICB across cancers. Mutation-derived neoepitopes presented on the tumor cell surface is believed to be recognized by T cells and are thus critical for tumor clearance. However, the capacity to mount a neoantigen T cell response and the kinetics in relation to ICB remain poorly understood. Methods: 24 pts with mUC were treated with atezolizumab (anti-PD-L1) 1200mg q3w on IMVigor 210 at MSKCC and included in here. Pt-specific neoepitopes were predicted based on whole-exome and RNA sequencing of pre-treatment archival tumors using the MuPeXI platform. Using DNA-barcode labelled pMHC multimers, we investigated CD8 T cell recognition of mutation-derived neoepitopes by screening pt PBMC samples pre- and post-treatment with atezolizumab (n = 85 PBMC samples). The kinetics of neoepitope-specific CD8 T cells were assessed for association with durable clinical benefit (DCB; defined as progression free survival > 6 mo). Results: Neoepitope peptide libraries of between 200-587 peptides were generated per pt (mean = 260 peptides per pt). 31 out of a combined 56 possible pt HLA types across the cohort were utilized for T cell analyses (mean four HLAs per pt). MHC multimer-based screening of pt PBMCs revealed detection of neoepitope-specific CD8 T cells in 22 of 24 pts pre-treatment (range one to 14 neoepitope responses) and 21 of 22 pts post-treatment (up to 273 weeks after trial start; one to 19 neoepitope responses). There were large inter- and intra-patient variations of neoepitope-specific CD8 T cell responses during treatment with the largest increases occurring at the 3-wk, post-treatment initiation timepoint. We observed that pts with DCB tend to raise a broader neoantigen T cell response than patients without DCB. 38% of pts without DCB and 67% of pts with DCB exhibited an increase in neoepitope-specific CD8 T cell responses within 3 wks of treatment initiation. Conclusions: Using high-throughput screening, pt-specific neoepitope reactive CD8 T cells could be detected pre- and post-treatment in pts with mUC treated with atezolizumab. Phenotypic characterization of neoepitope reactive CD8 T cells is ongoing. These data may help elucidate the dynamics and characteristics of the T cells of highest relevance to the ICB-induced, anti-tumor immune response.

Effect of NKTR-214 on the number and activity of CD8+ tumor infiltrating lymphocytes in patients with advanced renal cell carcinoma.

2017 ◽  
Vol 35 (6_suppl) ◽  
pp. 454-454 ◽  
Author(s):  
Michael E. Hurwitz ◽  
Adi Diab ◽  
Chantale Bernatchez ◽  
Cara L. Haymaker ◽  
Harriet M. Kluger ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Microenvironment ◽  
Cd8 T Cells ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Tumor Infiltrating Lymphocytes ◽  
Poor Response ◽  
Post Treatment ◽  
Open Label

454 Background: Patients with low baseline CD8+ T-cells within the tumor microenvironment (TILs) have a poor response to immune checkpoint inhibitors. Agents designed to specifically activate and expand CD8+ T cells may improve clinical outcomes in patients with low TILs. NKTR-214 is a CD-122-biased agonist designed to provide sustained signaling through the heterodimeric IL-2 receptor pathway (IL-2Rβɣ) and preferentially activate and expand NK and effector CD8+ T cells over CD4+ T regulatory cells. Methods: A dose escalation, open-label, trial was initiated to assess the safety of NKTR-214 and explore immune changes in the blood and tumor microenvironment in patients with advanced solid tumors. NKTR-214 was administered IV in an outpatient setting with initial dosing at 0.003 mg/kg. Pre and post treatment blood and tumor samples were analyzed for immune phenotyping, gene expression, T cell receptor diversity, and changes in the tumor microenvironment by immunohistochemistry. Results: Among 25 patients dosed, 15 had RCC ([email protected]/kg, [email protected]/kg, and [email protected]/kg). Treatment with NKTR-214 was well tolerated and the MTD was not reached. One patient experienced DLTs (Gr3 syncope and hypotension) at 0.012 mg/kg. There were no immune-related AEs. Of 12 patients evaluable for response, 75% had SD at their first on treatment scan. Of 5 patients, who were immune checkpoint naïve with ≥ 1 prior TKI treatments, 3 experienced tumor shrinkage, 1 with PR per RECIST 1.1 (unconfirmed). Interrogation of the tumor microenvironment revealed many significant immunological changes post treatment, including increase in total and proliferating NK, CD8+, and CD4+ T cells. There was good correlation between increase in activated CD4+ and CD8+ T cells in peripheral blood with an increase in T cell infiltrates within the tumor tissue. Conclusions: NKTR-214 increased immune infiltration in the tumor and anti-tumor activity in patients who previously progressed on TKIs, with a favorable safety profile. The ability to alter the immune environment and increase PD-1 expression on effectors T cells may improve the effectiveness of anti-PD-1 blockade. A trial combining NKTR-214 and nivolumab is enrolling. Clinical trial information: 02869295.

scholarly journals O82 A phase 1 dose escalation study of PRS-343, a HER2/4–1BB bispecific molecule, in patients with HER2-positive malignancies

2020 ◽  
Vol 8 (Suppl 1) ◽  
pp. A1.2-A2 ◽  
Author(s):  
Sarina Piha-Paul ◽  
Johanna Bendell ◽  
Anthony Tolcher ◽  
Sara Hurvitz ◽  
Amita Patnaik ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Dose Escalation ◽  
Phase 1 ◽  
Cd8 T Cell ◽  
Post Treatment ◽  
Primary Study ◽  
Biomarker Response ◽  
Active Dose

BackgroundAnticalin® proteins are recombinantly engineered human proteins based on lipocalins. PRS-343 is a first-in-class bispecific antibody-Anticalin fusion protein targeting the oncogenic tumor antigen HER2 and the costimulatory immune receptor 4-1BB on T and other immune cells. Here, we report the results of a phase 1 single-agent dose escalation trial in patients with HER2+ solid tumors.MethodsPRS-343 has been evaluated in sequential dose cohorts from 0.0005 to 8 mg/kg i.v. Doses were administered Q3W and the 8 mg/kg dose was also given Q2W. An accelerated titration design was utilized for the initial dose escalation followed by a modified 3+3 design and the option to back-fill cohorts. Dose-limiting toxicities (DLTs) were reported during the first cycle of each schedule. The primary study objectives include the safety profile and RP2D of PRS-343. Secondary objectives include ORR and DCR, PD biomarker response and PK profile. PD response was assessed in tumor biopsies (CD8+ T cell IHC) pre- and post- PRS-343 treatment.Results51 patients (median age 61.2 years, 61% female, 82% caucasian, 57% with more than three lines of prior therapy) with a variety of solid tumor indications [gastric/GEJ (n=19); BC (n=12); gynecological cancer (n=6); CRC (n=5); BTC (n=4); UC (n=2); melanoma, pancreatic and salivary duct (n=1 each)] have been treated with PRS-343. Based on pharmacokinetic analyses and observed kinetics of the CD8+ T cell expansion post-treatment, the low end of the active dose range is considered 2.5 mg/kg. 19 patients treated at active dose levels before the data cut-off on 09-06-2019 were evaluable for response [DCR 58% (11% confirmed PR) as per RECIST 1.1]. At the active doses, we observed significant and pronounced post-treatment expansion of CD8+ T cells particularly in the tumor nests, consistent with the MoA of PRS-343, while there was no increase in the doses below 2.5 mg/kg. The post-treatment expansion of CD8+ T cells was more pronounced in patients with a confirmed PR or prolonged SD. PRS-343 was very well tolerated, with no SAEs reported. The most frequent TRAEs were fatigue (9%), chills (6%) and diarrhea (5%) of mild to moderate severity. None qualified as a DLT.ConclusionsPRS-343 is the first molecule of its kind to demonstrate encouraging evidence of safety and clinical benefit with a correlative PD effect in a heavily pre-treated population. These initial data suggest that PRS-343, the first 4-1BB bispecific to enter clinical development, merits further investigation in clinical trials.Trial RegistrationNCT03330561

451 Combining Bempegaldesleukin (CD122-preferential IL-2 pathway agonist) and NKTR-262 (TLR7/8 agonist) pairs local innate activation with systemic CD8+ T cell expansion to enhance anti-tumor immunity

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A478-A478
Author(s):  
Annah Rolig ◽  
Daniel Rose ◽  
Saul Kivimae ◽  
Werner Rubas ◽  
William Redmond
Keyword(s):  
T Cells ◽  
T Cell ◽  
Nk Cells ◽  
Cd8 T Cells ◽  
Cell Expansion ◽  
Nk Cell ◽  
Tumor Regression ◽  
Cell Activity ◽  
Cd8 T Cell ◽  
Post Treatment

BackgroundPreviously, we demonstrated that radiation therapy (RT) combined with Bempegaldesleukin (BEMPEG;NKTR-214), a first-in-class CD122-preferential IL-2 pathway agonist, led to enhanced anti-tumor efficacy through a T cell-dependent mechanism. However, we observed only modest systemic responses to BEMPEG/RT across several murine tumor models. Therefore, we explored alternative approaches to improve systemic tumor-specific immunity. We evaluated whether intratumoral NKTR-262, a polymer-modified toll-like receptor (TLR) 7/8 agonist, combined with systemic BEMPEG treatment resulted in improved tumor-specific immunity and survival compared to BEMPEG combined with RT. We hypothesized that BEMPEG/NKTR-262 immunotherapy would promote synergistic activation of local immunostimulatory innate immune responses followed by systemic adaptive immunity to significantly improve tumor regression and overall survival.MethodsTumor-bearing mice (CT26; EMT6) received BEMPEG (0.8 mg/kg; iv), RT (12 Gy x 1), and/or intratumoral NKTR-262 (0.5 mg/kg). Flow cytometry was used to evaluate CD4+ and CD8+ T cell activation status in the blood and/or tumor (7 days post-treatment) and NK cell activity in the tumor (1, 3 days post-treatment). The contribution of specific immune subsets was determined by depletion of CD4+, CD8+, or NK cells. CD8+ T cell activity was determined in vitro by tracking apoptosis in an Incucyte assay. Data are representative of 1–2 independent experiments (n=5–14/group) and statistical significance was determined by 1-way ANOVA (p-value cut-off of 0.05).ResultsBEMPEG/NKTR-262 resulted in significantly improved survival compared to BEMPEG/RT. BEMPEG/NKTR-262 efficacy was NK and CD8+ T cell-dependent, while BEMPEG/RT primarily relied on CD8+ T cells. Response to BEMPEG/NKTR-262 was characterized by a significant expansion of activated CD8+ T cells (GzmA+; Ki-67+; ICOS+; PD-1+) in the blood, which correlated with reduced tumor size (p<0.05). In the tumor, NKTR-262/BEMPEG induced higher frequencies of GzmA+ CD8+ T cells exhibiting reduced expression of suppressive molecules (PD-1+, TIM-3+), compared to BEMPEG/RT. Indeed, CD8+ T cells isolated from BEMPEG/NKTR-262-treated tumors had greater cytolytic capacity than those from BEMPEG/RT-treated mice. CD8+ T cell expansion (blood) and activity (tumor) depended upon the initial NK response, as neither occurred in the absence of NK cells. BEMPEG/NKTR-262 uniquely induced the expansion of early and high effector NK cells.ConclusionsCombining BEMPEG with NKTR-262 lead to an early and robust NK cell expansion not observed in the BEMPEG/RT combination. The improved tumor regression and survival was dependent on the NKTR-262 driven expansion of NK cells. A clinical trial of BEMPEG/NKTR-262 for patients with metastatic solid tumors is in progress (NCT03435640).

scholarly journals Longitudinal Changes in Cd4+, Cd8+ T Cell Phenotype and Activation Marker Expression Following Antiretroviral Therapy Initiation among Patients with Cryptococcal Meningitis

2019 ◽  
Vol 5 (3) ◽  
pp. 63
Author(s):  
Alice Bayiyana ◽  
Samuel Okurut ◽  
Rose Nabatanzi ◽  
Godfrey Zziwa ◽  
David R. Boulware ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Antiretroviral Therapy ◽  
Cell Surface ◽  
Cd8 T Cells ◽  
Cryptococcal Meningitis ◽  
Cd8 T Cell ◽  
Cd4 T Cell ◽  
Effector Memory ◽  
Memory Subset

Despite improvement in the prognosis of HIV/AIDS (human immunodeficiency virus/acquired immune deficiency syndrome) patients on antiretroviral therapy (ART), cryptococcal meningitis (CM) still causes 10–15% mortality among HIV-infected patients. The immunological impact of ART on the CD4+ and CD8+ T cell repertoire during cryptococcal co-infection is unclear. We determined longitudinal phenotypic changes in T cell subsets among patients with CM after they initiated ART. We hypothesized that ART alters the clonotypic phenotype and structural composition of CD4+ and CD8+ T cells during CM co-infection. For this substudy, peripheral blood mononuclear cells (PBMC) were isolated at four time points from CM patients following ART initiation during the parent study (ClinicalTrials.gov number, NCT01075152). Phenotypic characterization of CD4+ and CD8+ T cells was done using T cell surface marker monoclonal antibodies by flow cytometry. There was variation in the expression of immunophenotypic markers defining central memory (CD27+CD45R0+), effector memory (CD45R0+CD27–), immune activation (CD38+ and Human Leucocyte Antigen DR (HLA-DR+), and exhaustion (Programmed cell death protein one (PD-1) in the CD4+ T cell subset. In comparison to the CD4+ T cell population, the CD8+ central memory subset declined gradually with minimal increase in the effector memory subset. Both CD4+ and CD8+ T cell immune exhaustion and activation markers remained elevated over 12 weeks. The relative surge and decline in the expression of T cell surface markers outlines a variation in the differentiation of CD4+ T cells during ART treatment during CM co-infection.

Class I–unrestricted noncytotoxic anti–HTLV-I activity of CD8+ T cells

Blood ◽  
2000 ◽  
Vol 96 (5) ◽  
pp. 1994-1995 ◽  
Author(s):  
Masako Moriuchi ◽  
Hiroyuki Moriuchi
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Mononuclear Cells ◽  
Membrane Filter ◽  
Cd8 T Cell ◽  
Class I ◽  
Type I ◽  
Peripheral Blood Mononuclear ◽  
Permeable Membrane

Abstract Although it is widely believed that viral clearance is mediated principally by the destruction of infected cells by cytotoxic T cells, noncytolytic antiviral activity of CD8+ T cells may play a role in preventing the progression to disease in infections with immunodeficiency viruses and hepatitis B virus. We demonstrate here that (1) replication of human T-lymphotropic virus type I (HTLV-I) is more readily detected from CD8+ T-cell–depleted (CD8−) peripheral blood mononuclear cells (PBMCs) of healthy HTLV-I carriers than from unfractionated PBMCs, (2) cocultures of CD8− PBMCs with autologous or allogeneic CD8+ T cells suppressed HTLV-I replication, and (3) CD8+ T-cell anti-HTLV-I activity is not abrogated intrans-well cultures in which CD8+ cells are separated from CD8− PBMCs by a permeable membrane filter. These results suggest that class I-unrestricted noncytolytic anti–HTLV-I activity is mediated, at least in part by a soluble factor(s), and may play a role in the pathogenesis of HTLV-I infection.

scholarly journals Immunodominant Cytomegalovirus Epitopes Suppress Subdominant Epitopes in the Generation of High-Avidity CD8 T Cells

Pathogens ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 956
Author(s):  
Kirsten Freitag ◽  
Sara Hamdan ◽  
Matthias J. Reddehase ◽  
Rafaela Holtappels
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Immune Escape ◽  
Cd8 T Cell ◽  
Antigenic Drift ◽  
Murine Cytomegalovirus ◽  
High Avidity ◽  
Infected Cells ◽  
Cd8 T Cell Memory

CD8+ T-cell responses to pathogens are directed against infected cells that present pathogen-encoded peptides on MHC class-I molecules. Although natural responses are polyclonal, the spectrum of peptides that qualify for epitopes is remarkably small even for pathogens with high coding capacity. Among those few that are successful at all, a hierarchy exists in the magnitude of the response that they elicit in terms of numbers of CD8+ T cells generated. This led to a classification into immunodominant and non-immunodominant or subordinate epitopes, IDEs and non-IDEs, respectively. IDEs are favored in the design of vaccines and are chosen for CD8+ T-cell immunotherapy. Using murine cytomegalovirus as a model, we provide evidence to conclude that epitope hierarchy reflects competition on the level of antigen recognition. Notably, high-avidity cells specific for non-IDEs were found to expand only when IDEs were deleted. This may be a host’s back-up strategy to avoid viral immune escape through antigenic drift caused by IDE mutations. Importantly, our results are relevant for the design of vaccines based on cytomegaloviruses as vectors to generate high-avidity CD8+ T-cell memory specific for unrelated pathogens or tumors. We propose the deletion of vector-encoded IDEs to avoid the suppression of epitopes of the vaccine target.

scholarly journals Relationship between PD-L1 expression, CD8+ T-cell infiltration and prognosis in intrahepatic cholangiocarcinoma patients

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Min Deng ◽  
Shao-Hua Li ◽  
Xu Fu ◽  
Xiao-Peng Yan ◽  
Jun Chen ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Intrahepatic Cholangiocarcinoma ◽  
Patient Survival ◽  
Disease Free Survival ◽  
Cd8 T Cell ◽  
Future Research ◽  
Programmed Death ◽  
Expression Rate

Abstract Background Programmed death- ligand 1 (PD-L1) seems to be associated with the immune escape of tumors, and immunotherapy may be a favorable treatment for PD-L1-positive patients. We evaluated intrahepatic cholangiocarcinoma (ICC) specimens for their expression of PD-L1, infiltration of CD8+ T cells, and the relationship between these factors and patient survival. Methods In total, 69 resections of ICC were stained by immunohistochemistry for PD-L1, programmed death factor-1 (PD-1), and CD8+ T cells. CD8+ T-cell densities were analyzed both within tumors and at the tumor-stromal interface. Patient survival was predicted based on the PD-L1 status and CD8+ T-cell density. Results The expression rate of PD-L1 was 12% in cancer cells and 51% in interstitial cells. The expression rate of PD-1 was 30%, and the number of CD8+ T-cells increased with the increase of PD-L1 expression (p < 0.05). The expression of PD-L1 in the tumor was correlated with poor overall survival(OS) (p = 0.004), and the number of tumor and interstitial CD8+ T-cells was correlated with poor OS and disease-free survival (DFS) (All p < 0.001). Conclusions The expression of PD-L1 in the tumor is related to poor OS, and the number of tumor or interstitial CD8+ T-cells is related to poor OS and DFS. For patients who lose their chance of surgery, PD-L1 immunosuppressive therapy may be the focus of future research as a potential treatment.

scholarly journals Direct and Indirect endocrine-mediated suppression of human endometrial CD8+T cell cytotoxicity

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Z. Shen ◽  
M. Rodriguez-Garcia ◽  
M. V. Patel ◽  
C. R. Wira
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Cytotoxic Activity ◽  
Cd8 T Cells ◽  
Immune Cells ◽  
Cd8 T Cell ◽  
Gynecological Cancers ◽  
Protective Strategies ◽  
T Cell Cytotoxicity

AbstractRegulation of endometrial (EM) CD8+T cells is essential for successful reproduction and protection against pathogens. Suppression of CD8+T cells is necessary for a tolerogenic environment that promotes implantation and pregnancy. However, the mechanisms regulating this process remain unclear. Sex hormones are known to control immune responses directly on immune cells and indirectly through the tissue environment. When the actions of estradiol (E2), progesterone (P) and TGFβ on EM CD8+T cells were evaluated, cytotoxic activity, perforin and granzymes were directly suppressed by E2 and TGFβ but not P. Moreover, incubation of polarized EM epithelial cells with P, but not E2, increased TGFβ secretion. These findings suggest that E2 acts directly on CD8+T cell to suppress cytotoxic activity while P acts indirectly through induction of TGFβ production. Understanding the mechanisms involved in regulating endometrial CD8+T cells is essential for optimizing reproductive success and developing protective strategies against genital infections and gynecological cancers.

scholarly journals Type I Interferons Regulate the Magnitude and Functionality of Mouse Polyomavirus-Specific CD8 T Cells in a Virus Strain-Dependent Manner

2016 ◽  
Vol 90 (10) ◽  
pp. 5187-5199 ◽  
Author(s):  
Qingsong Qin ◽  
Shwetank ◽  
Elizabeth L. Frost ◽  
Saumya Maru ◽  
Aron E. Lukacher
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cell Response ◽  
Cd8 T Cell ◽  
T Cell Response ◽  
Single Amino Acid ◽  
Type I ◽  
Type I Ifns ◽  
Vp1 Capsid Protein

ABSTRACTMouse polyomavirus (MPyV) is a ubiquitous persistent natural mouse pathogen. A glutamic acid (E)-to-glycine (G) difference at position 91 of the VP1 capsid protein shifts the profile of tumors induced by MPyV from an epithelial to a mesenchymal cell origin. Here we asked if this tropism difference affects the MPyV-specific CD8 T cell response, which controls MPyV infection and tumorigenesis. Infection by the laboratory MPyV strain RA (VP1-91G) or a strain A2 mutant with an E-to-G substitution at VP1 residue 91 [A2(91G)] generated a markedly smaller virus-specific CD8 T cell response than that induced by A2(VP1-91E) infection. Mutant A2(91G)-infected mice showed a higher frequency of memory precursor (CD127hiKLRG1lo) CD8 T cells and a higher recall response than those of A2-infected mice. Using T cell receptor (TCR)-transgenic CD8 T cells and immunization with peptide-pulsed dendritic cells, we found that early bystander inflammation associated with A2 infection contributed to recruitment of the larger MPyV-specific CD8 T cell response. Beta interferon (IFN-β) transcripts were induced early during A2 or A2(91G) infections. IFN-β inhibited replication of A2 and A2(91G)in vitro. Using mice lacking IFN-αβ receptors (IFNAR−/−), we showed that type I IFNs played a role in controlling MPyV replicationin vivobut differentially affected the magnitude and functionality of virus-specific CD8 T cells recruited by A2 and A2(91G) viral infections. These data indicate that type I IFNs are involved in protection against MPyV infection and that their effect on the antiviral CD8 T cell response depends on capsid-mediated tropism properties of the MPyV strain.IMPORTANCEIsolates of the human polyomavirus JC virus from patients with the frequently fatal demyelinating brain disease progressive multifocal leukoencephalopathy (PML) carry single amino acid substitutions in the domain of the VP1 capsid protein that binds the sialic acid moiety of glycoprotein/glycolipid receptors on host cells. These VP1 mutations may alter neural cell tropism or enable escape from neutralizing antibodies. Changes in host cell tropism can affect recruitment of virus-specific CD8 T cells. Using mouse polyomavirus, we demonstrate that a single amino acid difference in VP1 known to shift viral tropism profoundly affects the quantity and quality of the anti-polyomavirus CD8 T cell response and its differentiation into memory cells. These findings raise the possibility that CD8 T cell responses to infections by human polyomaviruses may be influenced by VP1 mutations involving domains that engage host cell receptors.

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