B7-CTLA4 interaction promotes cognate destruction of tumor cells by cytotoxic T lymphocytes in vivo

Blood ◽  
2002 ◽  
Vol 99 (8) ◽  
pp. 2880-2889 ◽  
Author(s):  
Xue-Feng Bai ◽  
Jinqing Liu ◽  
Kenneth F. May ◽  
Yong Guo ◽  
Pan Zheng ◽  
...  
Keyword(s):  
T Cell ◽  
Tumor Cells ◽  
T Cell Receptor ◽  
Antitumor Immunity ◽  
Clonal Expansion ◽  
Cell Receptor ◽  
Tumor Rejection ◽  
Effector Phase ◽  
Cell Clonal Expansion

Abstract Costimulatory molecules B7-1 and B7-2 (hereby collectively called B7) interact with CD28 and CTLA4 on T cells and promote antitumor immunity. The function of B7-CTLA4 interaction in antitumor CTL response remains controversial. Here we used CD28−/− and CD28+/− or CD28+/+ transgenic mice that express the T-cell receptor specific for an unmutated tumor antigen, P1A, and for tumor cells expressing a CTLA4-specific B7 mutant to evaluate the function of CD28-B7 and CTLA4-B7 interactions in induction and effector phases of antitumor immunity. We report that B7-CD28 and B7-CTLA4 interactions promote tumor rejection. However, this is achieved by distinct mechanisms. B7-CD28 interaction enhances T-cell clonal expansion, though a role for this interaction in the effector phase cannot be ruled out. In contrast, B7-CTLA4 interaction enhances the CTL-mediated destruction of tumors, but not T-cell clonal expansion.

T-cell receptor pharmacodynamics associated with survival and response to tremelimumab (T) in combination with durvalumab (D) in patients (pts) with unresectable hepatocellular carcinoma (uHCC).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 4087-4087
Author(s):  
Patricia McCoon ◽  
Young S Lee ◽  
Robin Kate Kelley ◽  
Violeta Beleva Guthrie ◽  
Song Wu ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
Single Agent ◽  
Clonal Expansion ◽  
Cell Receptor ◽  
Combination Regimen ◽  
Cell Counts ◽  
Significant Difference ◽  
Dose Dependent ◽  
Cell Clonal Expansion

4087 Background: Study 22, a phase 2 clinical study (NCT02519348) evaluating T (anti-CTLA-4) and D (anti-PD-L1) as monotherapies and in combination indicated the best efficacy-safety profile with a novel combination regimen containing a single, priming dose of T (T300+D). Additionally, an expansion of proliferative CD8+ lymphocytes at Day 15 was observed with T300+D that was associated with improved response. Here, an exploratory molecular analysis of peripheral blood T cell receptors is presented. Methods: Immune-checkpoint inhibitor-naïve pts were randomized to 1 of 2 T+D combinations: T300+D (T 300 mg [1 dose] + D 1500 mg, then D every 4 weeks [Q4W]) or T75+D (T 75 mg Q4W + D 1500 mg Q4W [4 doses], then D Q4W); or single agent D (1500 mg Q4W) or T (750 mg Q4W [7 doses] then Q12W). DNA was isolated from PAXgene-preserved whole blood collected at baseline and on Day 29 during the first cycle of Q4W dosing, and then underwent CDR3 sequencing of T-cell receptor β using the immunoSEQ Assay (Adaptive Biotechnologies, Seattle, WA). Associations with objective response rate (ORR) and overall survival (OS) were evaluated. Results: The number of evaluable pts, samples, and overall ORR and OS are provided (Table). Immunosequencing analysis did not reveal significant differences in baseline T-cell clonality across arms. Increased T-cell clonal expansion at Day 29 appeared to be T dose dependent (Table), with no significant difference in the median expansion between the D and T75+D arms. Across all arms, responders had a larger median number of expanded T-cell clones on Day 29 than nonresponders (77.5 vs 40), and this greater expansion trended with longer OS (Table). Further evaluation by arm demonstrated an increase in T-cell clonal expansion in responders vs nonresponders in the T300+D arm. Pts with T-cell expansion above the median in the T300+D and T75+D arms also exhibited longer OS. Both newly expanded and total expanded clones on Day 29 vs Day 1 were associated with improved OS. Conclusions: The observed T dose-dependent increase in T-cell clonal expansion trended with improved ORR and longer OS, with the greatest overall benefit seen with T300+D vs T75+D, D and T. This is consistent with the previously reported observation that T300+D led to the highest median proliferating CD8+ T-cell counts and radiographic response. Further work is needed to differentiate the relative contributions of CD4 and CD8 clonal expansion to increased efficacy. T300+D and D are being evaluated in the phase 3 HIMALAYA study (NCT03298451) in uHCC vs sorafenib. Funding: AstraZeneca. Clinical trial information: NCT02519348. [Table: see text]

scholarly journals Use of high throughput T cell receptor (TCR) DNA sequencing to characterize T cell infusion products and track clonal expansion in vivo

2014 ◽  
Vol 2 (S3) ◽  
Author(s):  
Madeleine Strohl ◽  
Hallie Graor ◽  
Mei Zhang ◽  
Isabelle Rivers-McCue ◽  
John Ammori ◽  
...  
Keyword(s):  
T Cell ◽  
Dna Sequencing ◽  
T Cell Receptor ◽  
High Throughput ◽  
Clonal Expansion ◽  
Cell Receptor

scholarly journals PD-L1/B7H-1 Inhibits the Effector Phase of Tumor Rejection by T Cell Receptor (TCR) Transgenic CD8+ T Cells

2004 ◽  
Vol 64 (3) ◽  
pp. 1140-1145 ◽  
Author(s):  
Christian Blank ◽  
Ian Brown ◽  
Amy C. Peterson ◽  
Mike Spiotto ◽  
Yoshiko Iwai ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Cd8 T Cells ◽  
Cell Receptor ◽  
Tumor Rejection ◽  
Effector Phase

scholarly journals Loss of T cell-mediated antitumor immunity after construct-specific downregulation of retrovirally encoded T-cell receptor expression in vivo

2008 ◽  
Vol 16 (2) ◽  
pp. 171-183 ◽  
Author(s):  
M P Rubinstein ◽  
M L Salem ◽  
A N Kadima ◽  
C L Nguyen ◽  
W E Gillanders ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
Antitumor Immunity ◽  
Cell Receptor ◽  
Receptor Expression

scholarly journals 161 Development of a CD8 co-receptor independent T cell receptor specific for tumor-associated antigen MAGE-A4 for next generation T cell-based immunotherapy

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A175-A175
Author(s):  
Kathrin Davari ◽  
Tristan Holland ◽  
Laura Prassmayer ◽  
Giulia Longinotti ◽  
Kenneth Ganley ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Cells ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Receptor Expression ◽  
T Cell Subsets ◽  
High Avidity

BackgroundThe cancer-testis antigen MAGE-A4 is an attractive target for T cell-based immunotherapy, especially for indications with unmet clinical need like non-small-cell lung carcinoma or triple-negative breast cancer. Overcoming high tumor burden using adoptive transfer of T cells modified to express a transgenic T cell receptor (TCR) demands optimal recognition of the corresponding target on tumor cells by the TCR-modified T cells (TCR-Ts). Here we describe the isolation and pre-clinical characterization of high avidity TCR-Ts expressing a human leucocyte antigen (HLA)-A*02:01-restricted MAGE-A4-specific TCR that is fully functional in T cells irrespective of CD4 or CD8 co-receptor expression.MethodsAn unbiased CD137-based sorting approach was first used to identify an immunogenic MAGE-A4-derived candidate epitope that was properly processed and presented on HLA-A2 molecules encoded by the HLA-A*02:01 allele. To isolate high avidity T cells via subsequent multimer sorting, an in vitro priming approach using HLA-A2-negative donors (allogeneic-HLA-restricted priming approach) was conducted to bypass central tolerance to this self-antigen. Pre-clinical parameters of safety and activity were assessed in a comprehensive set of in vitro and in vivo studies of the lead TCR candidate derived from a selected T cell clone.ResultsA TCR recognizing the MAGE-A4-derived decapeptide GVYDGREHTV was isolated from primed T cells of a non-tolerant HLA-A2-negative donor. The respective TCR-T cell product bbT485, expressing the lead TCR in T cells from healthy donors, was demonstrated pre-clinically to have a favorable safety profile and superior in vivo potency compared to TCR-Ts made using a TCR derived from an HLA-A2-positive donor bearing a tolerized T cell repertoire to self-antigens. The natural high avidity allogeneic (allo)-derived TCR was found to be CD8 co-receptor-independent, allowing effector functions to be elicited in transgenic CD4+ T helper cells. These CD4+ TCR-T cells not only supported an anti-tumor response by direct killing of MAGE-A4-positive tumor cells, but also upregulated hallmarks associated with helper function, such as CD154 expression and release of key cytokines upon tumor-specific stimulation.ConclusionsThe extensive pre-clinical assessment of safety and in vivo potency of this non-mutated high avidity, CD8 co-receptor-independent, MAGE-A4-specific HLA-A2 restricted TCR provide the basis for its use in clinical TCR-T immunotherapy studies. The ability of this co-receptor-independent TCR to activate all transduced T cells (irrespective of CD4 or CD8 expression) could potentially provide enhanced cellular responses in the clinical setting through the induction of functionally diverse T cell subsets that goes beyond what is currently tested in the clinic.

scholarly journals Recurrent T cell receptor rearrangements in the cytotoxic T lymphocyte response in vivo against the p815 murine tumor.

1996 ◽  
Vol 183 (2) ◽  
pp. 439-449 ◽  
Author(s):  
J P Levraud ◽  
C Pannetier ◽  
P Langlade-Demoyen ◽  
V Brichard ◽  
P Kourilsky
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
Cell Response ◽  
Cytotoxic T Lymphocyte ◽  
Tumor Infiltrating Lymphocytes ◽  
Cell Receptor ◽  
T Cell Response ◽  
Tumor Rejection ◽  
Mouse Tissues

P815 is a murine mastocytoma of DBA/2 origin which, although immunogenic, rapidly develops as a tumor in immunocompetent syngeneic hosts. In this report, we have studied, by a molecular approach, the in vivo alpha/beta T cell response to P815. Both situations of tumor growth after engraftment of naive animals or tumor rejection by preimmunized animals have been analyzed. The spectrum of T cell receptor beta chain rearrangements in the tumor-infiltrating lymphocytes was found to be highly variable among individual tumor-bearing mice. However, two rearrangements, one using V(beta)1 and J(beta)1.2 segments and one using the V(beta)1 and J(beta)2.5 segments, with conserved junctional regions, reproducibly emerge in most individuals. These two rearrangements thus correspond to "public" (recurrent) T cell clones, as opposed to "private" ones, which emerge in a seemingly stochastic fashion in immunized animals. Importantly, these public cells are observed in situations of either growth or rejection of the tumor. Quantification provides a clear increase in public T cells in secondary responses, but no obvious correlation provides between their level and primary tumor rejection. The V(beta)1- J(beta)1.2 rearrangement is borne by CTL directed against an antigen derived from P1A, a nonmutated mouse self protein which is expressed in P815 but not in normal mouse tissues except testis. A recurrent, public T cell response can thus be observed to an antigen derived from a self protein expressed by a tumor.

scholarly journals Fusion transcripts FYN-TRAF3IP2 and KHDRBS1-LCK hijack T cell receptor signaling in peripheral T-cell lymphoma, not otherwise specified

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Koen Debackere ◽  
Lukas Marcelis ◽  
Sofie Demeyer ◽  
Marlies Vanden Bempt ◽  
Nicole Mentens ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
Cell Lymphoma ◽  
Ex Vivo ◽  
Cell Receptor ◽  
T Cell Lymphoma ◽  
Peripheral T Cell Lymphoma ◽  
Fusion Transcripts ◽  
Not Otherwise Specified

AbstractPeripheral T-cell lymphoma (PTCL) is a heterogeneous group of non-Hodgkin lymphomas with poor prognosis. Up to 30% of PTCL lack distinctive features and are classified as PTCL, not otherwise specified (PTCL-NOS). To further improve our understanding of the genetic landscape and biology of PTCL-NOS, we perform RNA-sequencing of 18 cases and validate results in an independent cohort of 37 PTCL cases. We identify FYN-TRAF3IP2, KHDRBS1-LCK and SIN3A-FOXO1 as new in-frame fusion transcripts, with FYN-TRAF3IP2 as a recurrent fusion detected in 8 of 55 cases. Using ex vivo and in vivo experiments, we demonstrate that FYN-TRAF3IP2 and KHDRBS1-LCK activate signaling pathways downstream of the T cell receptor (TCR) complex and confer therapeutic vulnerability to clinically available drugs.

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