Distinct Tumor-Resident Memory HBV-Specific T Cell Responses Correlate with Relapse-Free Survival in Patients with HBV-Associated Hepatocellular Carcinoma

Abstract Thermal ablative therapies are standard treatments for localized hepatocellular carcinoma (HCC). In addition to local tumor destruction, ablation leads to abscopal effects in distant lesions most likely mediated by an anti-tumor immune response. Although microwave ablation (MWA) is increasingly substituting other ablative techniques, its systemic immunostimulatory effects are poorly studied. We analyzed tumor-specific immune responses in peripheral blood of HCC patients after thermal ablation with regard to T cell responses and disease outcome. While comprehensive flow cytometric analyses in sequential samples of a prospective patient cohort (n = 23) demonstrated only moderate effects of MWA on circulating immune cell subsets, fluorospot analyses of specific T cell responses against seven tumor-associated antigens (TTAs) revealed de-novo or enhanced tumor-specific immune responses in 30% of patients. This anti-tumor immune response was related to tumor control as Interferon-y and Interleukin-5 T cell responses against TAAs were more frequent in patients with a long-time remission (> 1 year) after MWA (7/16) compared to patients suffering from an early relapse (0/13 patients) and presence of tumor-specific T cell response (IFN-y and/or IL-5) was associated to longer progression-free survival (27.5 vs. 10.0 months). Digital image analysis of immunohistochemically stained archival HCC samples (n = 18) of patients receiving combined MWA and resection revealed a superior disease-free survival of patients with high T cell abundance at the time of thermal ablation (37.4 vs. 13.1 months). Our data demonstrates remarkable immune-related effects of MWA in HCC patients and provides additional evidence for a combination of local ablation and immunotherapy in this challenging disease.

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Abstract 5412: CCR4+CCR6+Th17 cells suppress autologous CD8+ T cell responses in patients with hepatocellular carcinoma

10.1158/1538-7445.am2012-5412 ◽

2012 ◽

Author(s):

Fei Zhao ◽

Bastian Hoechst ◽

Jaba Gamrekelashvili ◽

Lars Ormandy ◽

Torsten Voigtländer ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

T Cell ◽

Th17 Cells ◽

T Cell Responses ◽

Cd8 T Cell ◽

Cell Responses

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Cold-Inducible RNA Binding Protein as a Vaccination Platform to Enhance Immunotherapeutic Responses against Hepatocellular Carcinoma

Cancers ◽

10.3390/cancers12113397 ◽

2020 ◽

Vol 12 (11) ◽

pp. 3397

Author(s):

Leyre Silva ◽

Josune Egea ◽

Lorea Villanueva ◽

Marta Ruiz ◽

Diana Llopiz ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

T Cell ◽

Rna Binding ◽

Checkpoint Inhibitors ◽

Binding Protein ◽

Rna Binding Protein ◽

T Cell Responses ◽

Tumor Infiltrating Lymphocytes ◽

Cell Responses ◽

Tlr4 Ligand

Therapies based on immune checkpoint inhibitors (ICPI) have yielded promising albeit limited results in patients with hepatocellular carcinoma (HCC). Vaccines have been proposed as combination partners to enhance response rates to ICPI. Thus, we analyzed the combined effect of a vaccine based on the TLR4 ligand cold-inducible RNA binding protein (CIRP) plus ICPI. Mice were immunized with vaccines containing ovalbumin linked to CIRP (OVA-CIRP), with or without ICPI, and antigen-specific responses and therapeutic efficacy were tested in subcutaneous and orthotopic mouse models of liver cancer. OVA-CIRP elicited polyepitopic T-cell responses, which were further enhanced when combined with ICPI (anti-PD-1 and anti-CTLA-4). Combination of OVA-CIRP with ICPI enhanced ICPI-induced therapeutic responses when tested in subcutaneous and intrahepatic B16-OVA tumors, as well as in the orthotopic PM299L HCC model. This effect was associated with higher OVA-specific T-cell responses in the periphery, although many tumor-infiltrating lymphocytes still displayed an exhausted phenotype. Finally, a new vaccine containing human glypican-3 linked to CIRP (GPC3-CIRP) induced clear responses in humanized HLA-A2.01 transgenic mice, which increased upon combination with ICPI. Therefore, CIRP-based vaccines may generate anti-tumor immunity to enhance ICPI efficacy in HCC, although blockade of additional checkpoint molecules and immunosuppressive targets should be also considered.

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Regulatory T cell depletion enhances tumor specific CD8 T-cell responses, elicited by tumor antigen NY-ESO-1b in hepatocellular carcinoma patients, in vitro

International Journal of Oncology ◽

10.3892/ijo_00000561 ◽

2010 ◽

Vol 36 (4) ◽

Cited By ~ 16

Author(s):

Chen

Keyword(s):

Hepatocellular Carcinoma ◽

T Cell ◽

Tumor Antigen ◽

Regulatory T Cell ◽

T Cell Responses ◽

Cd8 T Cell ◽

Cell Depletion ◽

T Cell Depletion ◽

Cell Responses

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Hepatitis B virus (HBV) antigen-pulsed monocyte-derived dendritic cells from HBV-associated hepatocellular carcinoma patients significantly enhance specific T cell responses in vitro

Clinical & Experimental Immunology ◽

10.1111/j.1365-2249.2006.03281.x ◽

2006 ◽

Vol 147 (2) ◽

pp. 277-286 ◽

Cited By ~ 25

Author(s):

M. Shi ◽

S. Qian ◽

W.-W. Chen ◽

H. Zhang ◽

B. Zhang ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Dendritic Cells ◽

Hepatitis B Virus ◽

T Cell ◽

Hepatitis B ◽

T Cell Responses ◽

Cell Responses ◽

B Virus

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Association of Disparities in Known Minor Histocompatibility Antigens with Relapse-Free Survival and Graft-Versus-Host-Disease Upon Allogeneic Stem Cell Transplantation,

Blood ◽

10.1182/blood.v118.21.4136.4136 ◽

2011 ◽

Vol 118 (21) ◽

pp. 4136-4136

Author(s):

Willemijn Hobo ◽

Kelly Broen ◽

Walter J.F.M. van der Velden ◽

Annelies Greupink-Draaisma ◽

Niken Adisty ◽

...

Keyword(s):

Stem Cell ◽

Statistical Analysis ◽

T Cell ◽

Clinical Outcome ◽

Stem Cell Transplantation ◽

Relapse Free Survival ◽

Post Transplantation ◽

Free Survival ◽

Graft Versus Host ◽

Cell Responses

Abstract Abstract 4136 Purpose: Allogeneic stem cell transplantation (allo-SCT) can induce remission in patients with hematological malignancies due to graft-versus-tumor (GVT) responses. This, however, is often accompanied by graft-versus-host disease (GVHD). Both the GVT effect and GVHD are mediated by minor histocompatibility antigen (MiHA)-specific T cells recognizing peptide products from polymorphic genes that differ between recipient and donor. Here, we evaluated whether MiHA mismatches are associated with clinical outcome after partial T cell depleted allo-SCT. Patients and Methods: We retrospectively analyzed the impact of MiHA mismatches in a cohort of 327 patients who received a partially T cell-depleted allo-SCT because of a hematological malignancy. MiHA allele genotyping was performed by fluorescence-based competitive allele-specific PCR. Subsequently, a multivariable statistical analysis of immunogenic MiHA disparity rates and association with clinical outcome was performed. In addition, development of MiHA-specific T cell responses was assessed by dual-color tetramer staining. Results: Statistical analysis revealed that an autosomal MiHA disparity on DNA level associates with increased relapse-free survival in sibling transplants, especially in patients transplanted for multiple myeloma. In addition, mismatches for the ubiquitous Y chromosome-encoded MiHA resulted in more acute GVHD (grade 3–4), while other MiHA mismatches, either ubiquitous or restricted to hematopoietic cells, were not associated with GVHD. Finally, we demonstrated considerable differences between MiHA in the capability to induce in vivo T cell responses post-transplantation. Conclusion: These data support that autosomal MiHA contribute to the induction of GVT immunity providing a rationale for MiHA-based post-transplantation immunotherapy to prevent and treat persistent and recurrent cancer following allo-SCT. Disclosures: No relevant conflicts of interest to declare.

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