Unmasking the immune recognition of prostate cancer with CTLA4 blockade

Kwek, Serena S.; Cha, Edward; Fong, Lawrence

doi:10.1038/nrc3223

Cited by 49 publications

(35 citation statements)

References 84 publications

(85 reference statements)

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“…CTLA-4 binds to B7 ligands expressed on antigen-presenting cells (APCs) with higher affinity than the costimulatory molecule CD28, and both its gene and surface expression are induced during T cell activation upon APC interaction (1). By competing for and binding to B7 ligands, CTLA-4 inhibits T cell proliferation and cytokine expansion.…”

Section: Introductionmentioning

confidence: 99%

Improved Survival with T Cell Clonotype Stability After Anti–CTLA-4 Treatment in Cancer Patients

Klinger²,

et al. 2014

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Cytotoxic T lymphocyte–associated antigen-4 (CTLA-4) blockade can promote antitumor T cell immunity and clinical responses. The mechanism by which anti–CTLA-4 antibodies induces antitumor responses is controversial. To determine the effects of CTLA-4 blockade on the T cell repertoire, we used next-generation deep sequencing to measure the frequency of individual rearranged T cell receptor β (TCRβ) genes, thereby characterizing the diversity of rearrangements, known as T cell clonotypes. CTLA-4 blockade in patients with metastatic castration-resistant prostate cancer and metastatic melanoma resulted in both expansion and loss of T cell clonotypes, consistent with a global turnover of the T cell repertoire. Overall, this treatment increased TCR diversity as reflected in the number of unique TCR clonotypes. The repertoire of clonotypes continued to evolve over subsequent months of treatment. Whereas the number of clonotypes that increased with treatment was not associated with clinical outcome, improved overall survival was associated with maintenance of high-frequency clones at baseline. In contrast, the highest-frequency clonotypes fell with treatment in patients with short overall survival. Stably maintained clonotypes included T cells having high-avidity TCR such as virus-reactive T cells. Together, these results suggest that CTLA-4 blockade induces T cell repertoire evolution and diversification. Moreover, improved clinical outcomes are associated with less clonotype loss, consistent with the maintenance of high-frequency TCR clonotypes during treatment. These clones may represent the presence of preexisting high-avidity T cells that may be relevant in the antitumor response.

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Section: Introductionmentioning

confidence: 99%

Improved Survival with T Cell Clonotype Stability After Anti–CTLA-4 Treatment in Cancer Patients

Klinger²,

et al. 2014

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“…The recent FDA approval of two cancer immunotherapies, a vaccine (Sipuleucel-T) for treatment of prostate cancer (1), and an anti-CTLA-4 blocking antibody (ipilimumab) for treatment of metastatic melanoma (2), has highlighted the ability to modulate the immune system to attack tumors. An alternative therapeutic strategy, which is being actively pursued in multiple clinical settings, is adoptive T cell therapy (ACT), in which tumor-reactive T cells are generated and/or expanded ex vivo from T cells isolated from the blood or tumor of cancer patients and then infused back into the patient (3).…”

Section: Introductionmentioning

confidence: 99%

Cell-Intrinsic Abrogation of TGF-β Signaling Delays but Does Not Prevent Dysfunction of Self/Tumor-Specific CD8 T Cells in a Murine Model of Autochthonous Prostate Cancer

Chou

Schietinger

Liggitt

et al. 2012

The Journal of Immunology

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Adoptive T cell therapy (ACT) for the treatment of established cancers is actively being pursued in clinical trials. However, poor in vivo persistence and maintenance of anti-tumor activity of transferred T cells remain major problems. Transforming growth factor beta (TGFβ) is a potent immunosuppressive cytokine that is often expressed at high levels within the tumor microenvironment, potentially limiting T cell mediated anti-tumor activity. Here, we used a model of autochthonous murine prostate cancer to evaluate the effect of cell intrinsic abrogation of TGFβ signaling in self/tumor specific CD8 T cells used in ACT to target the tumor in situ. We found that persistence and anti-tumor activity of adoptively transferred effector T cells deficient in TGFβ signaling was significantly improved in the cancerous prostate. However, over time, despite persistence in peripheral lymphoid organs, the numbers of transferred cells in the prostate decreased and the residual prostate infiltrating T cells were no longer functional. These findings reveal that TGFβ negatively regulates the accumulation and effector function of transferred self/tumor specific CD8 T cells and highlight that, when targeting a tumor antigen that is also expressed as a self-protein, additional substantive obstacles are operative within the tumor microenvironment, potentially hampering the success of ACT for solid tumors.

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“…In particular, checkpoint inhibitors have emerged as a complementary avenue of clinical research in prostate cancer (11,12). These treatments target checkpoint molecules in the regulation of the immune system harnessing preexisting anticancer immune responses.…”

Section: Introductionmentioning

confidence: 99%

The Immune Checkpoint Regulator PD-L1 Is Highly Expressed in Aggressive Primary Prostate Cancer

Gevensleben

Dietrich

Golletz

et al. 2016

Clinical Cancer Research

182

189

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Purpose: Therapies targeting the programmed death 1 (PD-1)/ programmed death ligand 1 (PD-L1) pathway promote antitumor immunity and have shown promising results in various tumors. Preliminary data further indicate that immunohistochemically detected PD-L1 may be predictive for anti-PD-1 therapy. So far, no data are available on PD-L1 expression in primary prostate cancer.Experimental Design: Following validation of a monoclonal antibody, immunohistochemical analysis of PD-L1 expression was performed in two independent, well-characterized cohorts of primary prostate cancer patients following radical prostatectomy (RP), and resulting data were correlated to clinicopathological parameters and outcome.Results: In the training cohort (n ¼ 209), 52.2% of cases expressed moderate to high PD-L1 levels, which positively correlated with proliferation (Ki-67, P < 0.001), Gleason score (P ¼ 0.004), and androgen receptor (AR) expression (P < 0.001).Furthermore, PD-L1 positivity was prognostic for biochemical recurrence [BCR; P ¼ 0.004; HR, 2.37; 95% confidence interval (CI), 1.32-4.25]. In the test cohort (n ¼ 611), moderate to high PD-L1 expression was detected in 61.7% and remained prognostic for BCR in univariate Cox analysis (P ¼ 0.011; HR, 1.49; 95% CI, 1.10-2.02). The correlation of Ki-67 and AR with PD-L1 expression was confirmed in the test cohort (P < 0.001).In multivariate Cox analysis of all patients, PD-L1 was corroborated as independently prognostic for BCR (P ¼ 0.007; HR, 1.46; 95% CI, 1.11-1.92).Conclusions: We provide first evidence that expression of the therapy target PD-L1 is not only highly prevalent in primary prostate cancer cells but is also an independent indicator of BCR, suggesting a biologic relevance in primary tumors. Further studies need to ascertain if PD-1/PD-L1-targeted therapy might be a treatment option for hormone-na€ ve prostate cancers.

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Unmasking the immune recognition of prostate cancer with CTLA4 blockade

Cited by 49 publications

References 84 publications

Improved Survival with T Cell Clonotype Stability After Anti–CTLA-4 Treatment in Cancer Patients

Improved Survival with T Cell Clonotype Stability After Anti–CTLA-4 Treatment in Cancer Patients

Cell-Intrinsic Abrogation of TGF-β Signaling Delays but Does Not Prevent Dysfunction of Self/Tumor-Specific CD8 T Cells in a Murine Model of Autochthonous Prostate Cancer

The Immune Checkpoint Regulator PD-L1 Is Highly Expressed in Aggressive Primary Prostate Cancer

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