Depletion of regulatory T cells by anti-ICOS antibody enhances anti-tumor immunity of tumor cell vaccine in prostate cancer

Abstract Background: Prostate cancer recognized as a “cold” tumor has an immunosuppressive microenvironment in which regulatory T-cells (Tregs) usually represent a major role. Therefore, identifying a prognostic signature of Tregs has promising benefits of improving survival of prostate cancer patients. However, the prognostic signature based on Tregs-specific mRNAs for prostate cancer is lacking. Methods: We systematicly analyzed transcriptional profiles of Tregs and 19 other immune cell types using 42 purified immune cell datasets from GEO to identify Tregs-specific mRNAs, and develop and validate a prognostic signature of Tregs (named “TILTregSig”) for monitoring prognosis of prostate cancer using TCGA and ICGC datasets. We also applied the signature to five immunotherapy response datasets and GSCALite to analyze the potential of the TILTregSig for predicting CIT response and cancer therapeutic resistance.Results: We develop the TILTregSig comprising five mRNAs (SOCS2, EGR1, RRM2, TPP1 and C11orf54) for prostate cancer patients. We find that the TILTregSig is a stronger predictor for tumor immunity compared with tumor mutation burden (TMB) and glycolytic activity which have been reported as immune predictors. Further analyses indicate that the TILTregSig may influence tumor immunity mainly by mediating tumor-infiltrating Tregs. Moreover, the TILTregSig also shows promising potential for predicting cancer immunotherapy (CIT) response and therapeutic resistance in multiple cancers.Conclusions: Our study has highlighted the value of the TILTregSig as a prognostic biomarker of prostate cancer from a tumor-infiltrating Tregs perspective, and strengthened its potential application as predictor of CIT response and cancer therapeutic resistance, which warrants further.

Download Full-text

Local and systemic effects of an allogeneic tumor cell vaccine combining transgenic human lymphotactin with interleukin-2 in patients with advanced or refractory neuroblastoma

Blood ◽

10.1182/blood-2002-08-2493 ◽

2003 ◽

Vol 101 (5) ◽

pp. 1718-1726 ◽

Cited By ~ 93

Author(s):

Raphaël F. Rousseau ◽

Ann E. Haight ◽

Charlotte Hirschmann-Jax ◽

Eric S. Yvon ◽

Donna R. Rill ◽

...

Keyword(s):

T Cells ◽

Tumor Cell ◽

Cell Line ◽

Single Agent ◽

Interleukin 2 ◽

Cell Vaccine ◽

Tumor Vaccines ◽

Tumor Cell Vaccine ◽

Allogeneic Tumor ◽

Allogeneic Tumor Cell

In murine models, transgenic chemokine–cytokine tumor vaccines overcome many of the limitations of single-agent immunotherapy by producing the sequence of T-cell attraction followed by proliferation. The safety and immunologic effects of this approach in humans were tested in 21 patients with relapsed or refractory neuroblastoma. They received up to 8 subcutaneous injections of a vaccine combining lymphotactin (Lptn)– and interleukin-2 (IL-2)–secreting allogeneic neuroblastoma cells in a dose-escalating scheme. Severe adverse reactions were limited to reversible panniculitis in 5 patients and bone pain in 1 patient. Injection-site biopsies revealed increased cellularity caused by infiltration of CD4+ and CD8+ lymphocytes, eosinophils, and Langerhans cells. Systemically, the vaccine produced a 2-fold (P = .035) expansion of CD4+ T cells, a 3.5-fold (P = .039) expansion of natural killer (NK) cells, a 2.1-fold (P = .014) expansion of eosinophils, and a 1.6-fold (P = .049) increase in serum IL-5. When restimulated in vitro by the immunizing cell line, T cells collected after vaccination showed a 2.3-fold increase (P = .02) of T-helper (TH2)–type CD3+IL-4+cells. Supernatant collected from restimulated cells showed increased amounts of IL-4 (11.4-fold; P = .021) and IL-5 (8.7-fold;P = .002). Six patients had significant increases in NK cytolytic activity. Fifteen patients made immunoglobulin G (IgG) antibodies that bound to the immunizing cell line. Measurable tumor responses included complete remission in 2 patients and partial response in 1 patient. Hence, allogeneic tumor cell vaccines combining transgenic Lptn with IL-2 appear to have little toxicity in humans and can induce an antitumor immune response.

Download Full-text

PHASE I/II CLINICAL TRIAL OF AN ACTIVATED WHOLE TUMOR CELL VACCINE FOLLOWED BY TRANSFER OF IMMUNE T CELLS IN PATIENTS WITH MANTLE CELL LYMPHOMA

Hematological Oncology ◽

10.1002/hon.2438_72 ◽

2017 ◽

Vol 35 ◽

pp. 207-208 ◽

Cited By ~ 1

Author(s):

M. Frank ◽

M. Khodadoust ◽

M. Chu ◽

H. Kohrt ◽

R. Advani ◽

...

Keyword(s):

Clinical Trial ◽

T Cells ◽

Tumor Cell ◽

Phase I ◽

Mantle Cell Lymphoma ◽

Cell Lymphoma ◽

Cell Vaccine ◽

Tumor Cell Vaccine ◽

Mantle Cell

Download Full-text

Abstract A13: A combinatory treatment targeting CD25+ regulatory T cells and CTL-associated antigen-4 blockage enhanced anti-tumor immunity in the HLA-DR transgenic mouse model of prostate cancer

Cancer Research ◽

10.1158/1538-7445.prca2012-a13 ◽

2012 ◽

Vol 72 (4 Supplement) ◽

pp. A13-A13

Author(s):

Elena N. Klyushnenkova ◽

Richard B. Alexander

Keyword(s):

Prostate Cancer ◽

T Cells ◽

Regulatory T Cells ◽

Mouse Model ◽

Transgenic Mouse ◽

Tumor Immunity ◽

Transgenic Mouse Model ◽

Hla Dr ◽

Treatment Targeting

Download Full-text

Intratumoral administration of DNA-damaging chemotherapy-treated tumor cells to enhance therapeutic benefit of systemic immune checkpoint blockade in mouse cancer models.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.5_suppl.77 ◽

2020 ◽

Vol 38 (5_suppl) ◽

pp. 77-77

Author(s):

Ganapathy Sriram ◽

Lauren Milling ◽

Jung-Kuei Chen ◽

Wuhbet Abraham ◽

Darrell J. Irvine ◽

...

Keyword(s):

T Cells ◽

Tumor Cell ◽

Tumor Cells ◽

Cd8 T Cells ◽

Ex Vivo ◽

Cd8 T Cell ◽

Cell Vaccine ◽

Tumor Cell Vaccine ◽

Ifn Γ

77 Background: Immune checkpoint inhibition or ICI (antibodies to PD-1 and CTLA4), has shown promise in the treatment of some tumor types, especially in inducing durable remissions in advanced stage cancer patients. However, the majority of patients do not respond to ICI. Identifying combinations to enhance response to ICI is an urgent medical need. Methods: Murine tumor cell lines B16-Ova and MC-38-Ova were treated with DNA-damaging chemotherapeutic drugs, co-cultured with primary murine bone marrow derived dendritic cells (BMDC) followed by addition of OT-1 CD8+ T-cells and flow cytometric analysis of IFN-γ+ CD8+ T-cells. Mice bearing B16-Ova or MC-38 flank tumors were injected intra-tumorally with ex vivo chemotherapy-treated B16-Ova cells with or without systemic ICI. Tumor cross-sectional area was measured using calipers. Intra-tumoral DC and circulating H2-Kb/SIINFEKL-specific CD8+ T-cells were analyzed by flow cytometry. Results: Etoposide and mitoxantrone-treated B16-Ova and MC-38-Ova tumor cells, when co-cultured with BMDC, efficiently promote IFN- γ induction in OT-1 CD8+ T-cells. This was abrogated by co-treatment of tumor cells with Necrostatin-1 but not ZVAD-FMK. Intra-tumoral injection of ex vivo etoposide-treated tumor cells, with systemic ICI, increases the numbers of intra-tumoral CD103+ DC, the frequency of circulating H2-Kb/SIINFEKL-specific CD8+ T-cells and significantly improves survival. The tumor cell vaccine/systemic ICI combination, but not ICI alone, induced complete tumor regressions in a subset of mice. This is abrogated in BATF3-deficient mice. Conclusions: Etoposide and mitoxantrone-treated tumor cells efficiently promote BMDC-mediated CD8+ T-cell priming, in a tumor cell RIPK1 activity-dependent but caspase-independent manner. Intra-tumoral administration of the DNA-damage induced tumor cell vaccine in vivo, in combination with systemic ICI, enhances anti-tumor CD8+ T-cell responses, tumor-free and overall survival, and anti-tumor immunological memory. This enhancement in therapeutic efficacy is dependent on BATF3+ DC in vivo.

Download Full-text