T-cell death and cancer immune tolerance

Lu, Binfeng; Finn, Olivera J.

doi:10.1038/sj.cdd.4402274

Cited by 90 publications

(77 citation statements)

References 110 publications

(156 reference statements)

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“…[22][23][24] One reason why malignant B cells evade the immune system is that they lack expression of some important accessory molecules necessary for the efficient activation of antigen-specific T cells. Recent efforts have focused on changing the phenotype of B-cell tumors through the transduction of costimulatory molecules such as CD40L.…”

Section: Discussionmentioning

confidence: 99%

Adenovirus-mediated LIGHT gene modification in murine B-cell lymphoma elicits a potent antitumor effect

Liu

et al. 2010

Cell Mol Immunol

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Here, we investigated the antitumor effect of adenovirus-mediated gene transfer of LIGHT, the tumor-necrosis factor (TNF) superfamily member also known as TNFSF14, in the murine A20 B-cell lymphoma. LIGHT gene modification resulted in upregulated expression of Fas and the accessory molecule-intercellular adhesion molecule-1 (ICAM-1) on A20 cells and led to enhanced A20 cell apoptosis. LIGHT-modified A20 cells effectively stimulated the proliferation of T lymphocytes and interferon (IFN)-c production in vitro. Immunization of BALB/c mice with a LIGHT-modified A20 cell vaccine efficiently elicited protective immunity against challenge with the parental tumor cell line. Adenovirus-mediated gene transfer of LIGHT by intratumoral injection exerted a very potent antitumor effect against pre-existing A20 cell lymphoma in BALB/c mice. This adenovirus-mediated LIGHT therapy induced substantial splenic natural killer (NK) and cytotoxic T lymphocyte (CTL) activity, enhanced tumor infiltration by inflammatory cells and increased chemokine expression of CC chemokine ligand 21 (CCL21), IFN-inducible protein-10 (IP-10) and monokine induced by IFN-c (Mig) from tumor tissues. Thus, adenovirus-mediated LIGHT therapy might have potential utility for the prevention and treatment of B-cell lymphoma.

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Section: Discussionmentioning

confidence: 99%

Adenovirus-mediated LIGHT gene modification in murine B-cell lymphoma elicits a potent antitumor effect

Liu

et al. 2010

Cell Mol Immunol

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“…We do not know whether inactivation of surviving CTLs was due to exhaustion, anergy, or a novel mechanism. Exhaustion and anergy often result from longterm (several days to weeks) interaction between T cells and APCs (41,42), but we observed deletion and functional CTL impairment within 2 d. Although several mechanisms of antitumor T cell tolerance have been documented (43), little progress has been made toward characterizing APCs that mediate CTL inactivation (2). The purpose of the current study was to establish the Ag specificity and dissect the contribution of different APCs to CTL impairment.…”

Section: Discussionmentioning

confidence: 99%

Rapid Deletion and Inactivation of CTLs upon Recognition of a Number of Target Cells over a Critical Threshold

Prato

Zhan

Mintern

et al. 2013

The Journal of Immunology

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Initiation of CTL responses against foreign pathogens also primes anti-self CTLs. Mechanisms of CTL inactivation inhibit anti-self CTLs to prevent tissue damage. These mechanisms are exploited by pathogens and tumors to evade the immune response, and present a major hurdle to adoptive CTL therapies. It is unclear whether CTL inactivation is Ag specific and, if so, which APCs are involved. Potential candidates include the target cells themselves, dendritic cells, myeloid-derived suppressor cells, and macrophages. In this study, we show that lymphoma-specific CTLs are rapidly deleted in an Ag-specific manner after adoptive transfer into lymphoma-bearing mice, and the surviving CTLs are functionally impaired. The only APCs responsible were the target cells directly presenting Ag, notwithstanding the presence of myeloid-derived suppressor cells, and CD8+ dendritic cells cross-presenting tumor Ag. The capacity to inactivate CTLs critically depended on the number of tumor/target cells; small numbers of targets were readily killed, but a large number caused quick deletion and functional inactivation of the CTLs. Application of mild, noninflammatory, and nonlymphoablative chemotherapy to specifically reduce tumor burden before CTL injection prevented CTL deletion and inactivation and allowed eradication of tumor. Our results advocate the use of adoptive CTL therapy soon after mild chemotherapy. They also suggest a simple mechanism for Ag-specific impairment of anti-self CTLs in the face of an active anti-foreign CTL response.

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“…7,8 As a result of the anti-AML effects of DLI and with the observation that antitumor-specific cytotoxic T cells (CTLs) can be generated in vitro from cancer patients, adoptive CTL therapy has been proposed for decades as cancer treatment. [9][10][11][12][13][14] However, the adoptive transfer of anti-AML-reactive CTLs alone has not solved the problem of AML disease recurrence. 15 In patients with chronic myelogenous leukemia, a complete remission was achieved in a patient with accelerated-phase disease after adoptive treatment with leukemia-reactive CTLs.…”

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confidence: 99%

Depletion of endogenous tumor-associated regulatory T cells improves the efficacy of adoptive cytotoxic T-cell immunotherapy in murine acute myeloid leukemia

Zhou

Bucher

Munger

et al. 2009

Blood

132

113

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IntroductionAcute myeloid leukemia (AML) with unfavorable cytogenetics has a poor outcome, even when treated with aggressive chemotherapy. 1,2 With chemoradiotherapy and hematopoietic stem cell transplantation, a graft-versus-leukemia effect can be observed even in patients with unfavorable cytogenetics. 3 Although donor lymphocyte infusion (DLI) given as adoptive immunotherapy after hematopoietic stem cell transplantation has improved the outcomes of certain types of leukemia, 4-6 for patients with AML, DLI has been less effective likely due at least in part to its rapid tumor progression. 7,8 As a result of the anti-AML effects of DLI and with the observation that antitumor-specific cytotoxic T cells (CTLs) can be generated in vitro from cancer patients, adoptive CTL therapy has been proposed for decades as cancer treatment. [9][10][11][12][13][14] However, the adoptive transfer of anti-AML-reactive CTLs alone has not solved the problem of AML disease recurrence. 15 In patients with chronic myelogenous leukemia, a complete remission was achieved in a patient with accelerated-phase disease after adoptive treatment with leukemia-reactive CTLs. 16 In rodents with minimal disease, CTL adoptive transfer also has not been uniformly curative despite the early transfer of large numbers of anti-AML-reactive CTLs. 17,18 Enhancing CTL function in vivo via the administration of supportive cytokine therapy such as interleukin-2 (IL-2), 20 and interferons 21 can improve antitumor efficacy but has been associated with substantial side effects. Therefore, recent studies have focused on eliminating the suppressive factors in the tumor environment to circumvent CTLs from inhibition. 22,23 T-regulatory cells (Tregs) are important regulators of immune responses in transplantation, 24,25 allergy, 26,27 and autoimmune disease. 28,29 In AML patients, the frequency of Tregs was noted to be significantly higher compared with healthy persons, likely due to increased proliferation. 30 Human AML cells have been noted to favor the conversion of CD4 ϩ 25 Ϫ T cells into Tregs via modulation of tryptophan catabolism. 31 Tregs that have been recruited to, or converted either before migration into or within the tumor environment, can have a profound inhibition on T cell-mediated immune response. 32 Multiple mechanisms have been defined to be responsible for the suppression, including secretion of transforming growth factor-␤ 33,34 and IL-10, 33,34 as well as inhibition of dendritic cell (DC) maturation. 33,35 Despite the great potential for Treg depletion in cancer therapies, the efficacy has been limited to prophylactic settings where depletion of Tregs is given before the establishment of tumor. 36,37 The present studies were undertaken to determine whether endogenous Tregs present at the site of AML dissemination constrained the antileukemia efficacy of anti-AML CTL adoptive transfer in a rodent model as a prelude to future clinical trials. We observed that AML progression correlated with increased Tregs at the sites of AML disease. Incr...

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T-cell death and cancer immune tolerance

Cited by 90 publications

References 110 publications

Adenovirus-mediated LIGHT gene modification in murine B-cell lymphoma elicits a potent antitumor effect

Adenovirus-mediated LIGHT gene modification in murine B-cell lymphoma elicits a potent antitumor effect

Rapid Deletion and Inactivation of CTLs upon Recognition of a Number of Target Cells over a Critical Threshold

Depletion of endogenous tumor-associated regulatory T cells improves the efficacy of adoptive cytotoxic T-cell immunotherapy in murine acute myeloid leukemia

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