ライフサイエンスコーパス: CTLA-4

1 cytotoxic T lymphocyte-associated protein 4 (CTLA-4).

2 ve ligand, cytotoxic T lymphocyte antigen 4 (CTLA-4).

3 cytotoxic-T-lymphocyte-associated protein-4 (CTLA-4).

4 cytotoxic-T-lymphocyte-associated protein-4 (CTLA-4).

5 hways and checkpoints such as PD-1/PD-L1 and CTLA-4.

6 on as well as cell-to-cell contact involving CTLA-4.

7 while exploiting the coinhibitory effects of CTLA-4.

8 had high levels of PD-1 and coexpression of CTLA-4.

9 nction of inhibitory receptors such as PD-1, CTLA-4, 2B4, Tim-3, and LAG-3 has shown promise for augm

10 nstituted "humanized" mice treated with anti-CTLA-4 Ab (ipilimumab) develop autoimmune disease charac

11 he latter could be further augmented by anti-CTLA-4 Ab to achieve tumor eradication and immunological

12 However, whether CTLA-4 acts simply to veto the activation of certain clo

13 ty of checkpoint blockade, Abs against PD-1, CTLA-4 alone, or in combination have distinct immunologi

14 n use CTLA-4 to elicit suppression; however, CTLA-4 also operates in conventional T cells, reputedly

15 cytotoxic T-lymphocyte-associated protein 4 (CTLA-4; an inhibitory molecule classically expressed on

16 sion of the minor isoform ligand-independent CTLA-4 and a reduction in diabetes has become widely acc

17 Combination therapy with alpha-CTLA-4 and alpha-PD-1 has shown significant clinical res

18 Thus, our findings indicate that anti-CTLA-4 and anti-PD-1 checkpoint-blockade-induced immune

19 However, even when using anti-CTLA-4 and anti-PD-1 in combination, approximately half

20 Tregs expressed the suppressive markers CTLA-4 and CD39, were functionally suppressive, and were

21 e with mRNA up-regulation of PD-L1, PD-1 and CTLA-4 and greater sensitivity to DNA-damaging agents in

22 the inhibitory checkpoint receptors PD-1 and CTLA-4 and have improved life expectancy for patients ac

23 ipilimumab contacts the front beta-sheet of CTLA-4 and intersects with the CTLA-4:Beta7 recognition

24 dies targeting T cell coinhibitory receptors CTLA-4 and PD-1 (programmed death-1) that have shown act

25 als showed significantly lower expression of CTLA-4 and PD-1 as well as lower inflammation, despite c

26 lorectal cancer remain largely refractory to CTLA-4 and PD-1 blockade.

27 -blocking antibodies against targets such as CTLA-4 and PD-1 can cure melanoma and non-small cell lun

28 ting the immune checkpoint molecules such as CTLA-4 and PD-1 have achieved durable responses in melan

29 dies targeting checkpoint inhibitors such as CTLA-4 and PD-1 have proven to be highly effective for t

30 unprecedented responses through blockade of CTLA-4 and PD-1 immune checkpoint pathways.

31 dels, we report that concomitant blockade of CTLA-4 and PD-1 improves anti-tumour immune responses an

32 knowledge about inhibitory receptors such as CTLA-4 and PD-1 into the cancer clinic highlights the op

33 eron gamma single positivity, an increase in CTLA-4 and PD-1, and a decrease in CD127 expression (all

34 ese monoclonal antibodies, developed against CTLA-4 and PD-1, block immune-inhibitory receptors on ac

35 Co-inhibitory receptors, such as CTLA-4 and PD-1, have an important role in regulating T

36 ess of blockade of the checkpoint modulators CTLA-4 and PD-1, have been developed without clear ident

37 T cells expressing the inhibitory molecules CTLA-4 and PD-1, which correlated with elevated inflamma

38 ill fail to respond to therapies that target CTLA-4 and PD-1.

39 nes, CD127 positivity, and low expression of CTLA-4 and PD-1.

40 Principles learned during the development of CTLA-4 and PD-1/PD-L1 approaches will likely be used as

41 Combination approaches involving CTLA-4 and PD-1/PD-L1 blockade are being investigated to

42 Treatment with both CTLA-4 and PD-1/PD-L1 blockade is associated with a uniq

43 rapies targeting immune checkpoint molecules CTLA-4 and PD-1/PD-L1 have advanced the field of cancer

44 gulate T-cell immune responses, such as CD80/CTLA-4 and PD-1/PD1-L, amplifying preexisting immunity a

45 vely blunts CD28 costimulation while sparing CTLA-4 and PD-L1 coinhibitory signals.

46 sts blunt T cell costimulation while sparing CTLA-4 and PD-L1-dependent coinhibitory signals.

47 ory CD8(+) T cells in mice treated with anti-CTLA-4 and rapamycin during immunization.

48 t-in-class immunotherapeutic for blockade of CTLA-4 and significantly benefits overall survival of pa

49 includes the Ig superfamily members CD28 and CTLA-4 and their ligands CD80 and CD86.

50 NK cells with IL-2 induces the expression of CTLA-4 and upregulates CD28.

51 easing use of ICB, predictors of response to CTLA-4 and/or PD-1 blockade represent unmet clinical nee

52 Ipilimumab (CTLA-4) and pembrolizumab (PD-1) are approved by the US

53 targeting cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed cell death-1 (PD-1) has significa

54 IM-3, like cytotoxic T lymphocyte antigen 4 (CTLA-4) and programmed death 1 (PD-1), is being targeted

55 cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and programmed death receptor 1 (PD-1) were inef

56 ional T cell proliferation via both surface (CTLA-4) and secreted (IL-10, TGF-beta, and IL-35) mediat

57 cytotoxic T-lymphocyte-associated Protein 4 (CTLA-4) and the induction of T-cell tolerance.

58 cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and the programmed cell death protein 1 pathway

59 cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and the programmed cell death protein 1 pathways

60 ocyte activation gene 3, KLRG1, CD103, ICOS, CTLA-4, and granzyme B.

61 A strong correlation between PD-1, but not CTLA-4, and HIV-1-specific T-cell proliferation was seen

62 The family includes CD28, CTLA-4, and ICOS as well as other proteins, including PD

63 block inhibitory T-cell pathways (i.e. PD-1, CTLA-4, and IDO); and (iv) adoptive cell transfer therap

64 lower inhibitory receptor expression (PD-1, CTLA-4, and the apoptosis-inducing Fas death receptor) c

65 ) T cells, turnover of the effector molecule CTLA-4, and their suppressive activity in vitro were inc

66 hension of the underlying mechanisms of anti-CTLA-4- and anti-PD-1-induced tumor rejection.

67 nd anergy (cytotoxic T lymphocyte antigen 4 [CTLA-4] and programmed death [PD]-1).

68 though combination checkpoint blockade (anti-CTLA-4 + anti-PD-1) was ineffective against BRAFi-resist

69 However, the triple combination of anti-CTLA-4, anti-PD-1, and G47Delta-mIL12 cured most mice in

70 nterrupting immune checkpoints, such as anti-CTLA-4, anti-PD-1, anti-PD-L1, and others in early devel

71 ore, combining bicarbonate therapy with anti-CTLA-4, anti-PD1, or adoptive T-cell transfer improved a

72 Remarkably, short-term blockade with anti-CTLA-4 antibody in wild-type mice is sufficient to elici

73 anti-PD-L1 antibody durvalumab and the anti-CTLA-4 antibody tremelimumab might provide greater antit

74 anti-PD-1 antibody) plus ipilimumab (an anti-CTLA-4 antibody) compared with ipilimumab alone.

75 notherapy, in particular treatment with anti-CTLA-4 antibody.

76 odies to patients who express high levels of CTLA-4 antigen in the pituitary can cause an aggressive

77 CTLA-4 antigen was expressed by pituitary endocrine cell

78 CD28 and CTLA-4 are members of a family of immunoglobulin-related

79 kpoint inhibitors, including those targeting CTLA-4/B7 and the PD-1/PD-L1 inhibitory pathways, are no

80 beta-sheet of CTLA-4 and intersects with the CTLA-4:Beta7 recognition surface, indicating that direct

81 Here, we provide an updated view of CTLA-4 biology, reviewing the established features of th

82 CTLA-4 expression on regulatory T cells, and CTLA-4 blockade alongside IL-2 treatment in vivo prevent

83 CTLA-4 blockade and granulocyte-macrophage colony-stimul

84 e that combining seemingly opposite signals, CTLA-4 blockade and rapamycin-mediated mammalian target

85 We find that the antitumor effects of CTLA-4 blockade depend on distinct Bacteroides species.

86 articles have also been published describing CTLA-4 blockade in cancer immunotherapy and its side eff

87 In a Friend retrovirus infection model, CTLA-4 blockade in particular was able to improve contro

88 Sensitivity to PD-1 and CTLA-4 blockade in patients with advanced NSCLC and mela

89 olyI:C and CpG was superior to combined PD-1/CTLA-4 blockade in sensitizing tumors to anti-ErbB2 mAb

90 CTLA-4 blockade increased IFN-gamma and CD40L production

91 Pathway analysis revealed that CTLA-4 blockade induces a proliferative signature predom

92 h a reduction in Ca(2+) flux in B cells, and CTLA-4 blockade inhibited the effects of Tregs on anergi

93 te that combining antigen-specific CTLs with CTLA-4 blockade is safe and produces durable clinical re

94 Because CTLA-4 blockade leads to proliferation of circulating T

95 on followed by early IL-2 treatment and anti-CTLA-4 blockade resulted in lower memory CD8 T cell numb

96 Here, we review these 2 diseases and CTLA-4 blockade therapy, emphasizing the crucial role of

97 negative tumors, the combination of PD-1 and CTLA-4 blockade was more effective than either agent alo

98 y glands of six cancer patients treated with CTLA-4 blockade, one with clinical and pathologic eviden

99 roidales in the immunostimulatory effects of CTLA-4 blockade.

100 mours when used in combination with systemic CTLA-4 blockade.

101 ve the potential to increase the efficacy of CTLA-4 blockade.

102 ragilis were associated with the efficacy of CTLA-4 blockade.

103 ther systemic GM-CSF (sargramostim) enhances CTLA-4 blockade.

104 nd robust CTLA-4 expression, in this context CTLA-4 blocking Abs had no impact on the response.

105 The study suggests that administration of CTLA-4 blocking antibodies to patients who express high

106 CTLA-4 can act by down-regulating CD80 and CD86 on antig

107 ent of immune-related consequences from anti-CTLA-4 cancer therapy.

108 e found to express TCRalpha, TCRbeta, CD152 (CTLA-4), CD154 (CD40L), T-bet, GATA-3, and STAT-1.

109 These studies present the CTLA-4-CD28-CD80/CD86 axis as a potential target to acce

110 CD4(+)FOXP3(+) intratumoral Treg expressing CTLA-4, CD39, and TGFbeta.

111 In contrast, in settings where CTLA-4(+) cells were present as "regulators," inhibition

112 immunotherapeutic responses associated with CTLA-4 checkpoint blockade.

113 rrent cytotoxic T-cell lymphocyte antigen-4 (CTLA-4) checkpoint blockade might enhance the antitumor

114 cytotoxic T-lymphocyte-associated antigen 4 [CTLA-4] checkpoint inhibitor) have been shown to have co

115 Modern immune therapies (PD-1/PD-L1 and CTLA-4 checkpoints blockade and adoptive cell transfer)

116 Blockade of the PD-1 and CTLA-4 checkpoints is proving to be an effective and dur

117 cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), cluster of differentiation (CD) 160, and CD244

118 These data support a model in which CTLA-4 control of immunity goes beyond vetoing T-cell pr

119 sponses, the immunological contexts in which CTLA-4 controls immune responses are not well defined.

120 molecules, including Foxp3, CD25, Nrp-1 and CTLA-4, coupled with a loss of Treg suppressive function

121 Recently, interactions mediated via the CTLA-4 cytoplasmic domain have been shown to preferentia

122 We propose that the function of CTLA-4 cytoplasmic domain is not to transmit inhibitory

123 mma, IFNalpha, interleukin-2, interleukin-7, CTLA-4 (cytotoxic T-lymphocyte-associated protein 4), T-

124 Although both PD-1 and CTLA-4 dampen the T cell activation, the in vivo effects

125 Heterozygous CTLA-4 deficiency has been reported as a monogenic cause

126 er recently described diseases, CHAI/LATAIE (CTLA-4 deficiency) and PASLI (PI3K dysregulation), as ad

127 imately the consequence of treatment-induced CTLA-4 deficiency.

128 c diseases that directly or indirectly cause CTLA-4 deficiency.

129 de, and conversely to treat autoimmunity and CTLA-4 deficiency.

130 Here we report that T cells in CTLA-4-deficient mice show spontaneous T-follicular help

131 CTLA-4 deleted T reg cells remained functionally suppres

132 Treg-mediated CTLA-4-dependent downregulation of CD80/CD86 on DCs was

133 low numbers of APC or low levels of ligand, CTLA-4-dependent suppression was highly effective wherea

134 Anti-CTLA-4 enhances T cell responses, including production o

135 g to the same class of receptors as PD-1 and CTLA-4, exhibit unique functions, especially at tissue s

136 slands in Treg-specific demethylated region, CTLA-4 exon 2, and glucocorticoid-induced TNFR exon 5, w

137 of resting T cell responses was dependent on CTLA-4 expression and specifically related to the number

138 d expansion of Foxp3(+) iTregs with enhanced CTLA-4 expression and suppressive capability, comparable

139 Assessing total CTLA-4 expression levels was found to be optimal when re

140 Importantly, OX40 and CTLA-4 expression on CD8 T cells was critical for promot

141 chanistically, early IL-2 treatment enhanced CTLA-4 expression on regulatory T cells, and CTLA-4 bloc

142 ted FoxP3, ICOS, and CTLA-4 expression, with CTLA-4 expression strikingly increased in all Treg subse

143 This high pituitary CTLA-4 expression was associated with T-cell infiltratio

144 Pituitary CTLA-4 expression was confirmed in a validation group of

145 PD-1 and CTLA-4 expression was significantly markedly reduced in

146 ed extensive T cell proliferation and robust CTLA-4 expression, in this context CTLA-4 blocking Abs h

147 ecently reported for LRBA, indirectly affect CTLA-4 expression, resulting in clinically similar disor

148 profiles, such as elevated FoxP3, ICOS, and CTLA-4 expression, with CTLA-4 expression strikingly inc

149 ersely correlated with PD-L1, PD-1, CD80 and CTLA-4 expression.

150 and lower cytotoxic T-lymphocyte antigen 4 (CTLA-4) expression than those in the blood.

151 increased cytotoxic T lymphocyte antigen-4 (CTLA-4) expression, and an enhanced suppressive capacity

152 of melanoma patients with antibodies against CTLA-4 favored the outgrowth of B. fragilis with antican

153 was reduced in inflamed ear tissue, whereas CTLA-4(+)Foxp3(+) Treg frequencies were augmented.

154 Cetuximab expanded CTLA-4(+)FOXP3(+) Treg in vitro, in part, by inducing de

155 lysosomal-blocking compounds, distinguished CTLA-4 from LRBA mutations.

156 CTLA-4 functionally replaced Treg cells in trans to resc

157 the primary driver of Treg proliferation and CTLA-4 functions as the main brake but is likely depende

158 it compared with all other treatments except CTLA-4/granulocyte macrophage colony-stimulating factor.

159 nhibition of coinhibitory receptors PD-1 and CTLA-4 had no effect.

160 en together, mutations in CTLA4 resulting in CTLA-4 haploinsufficiency or impaired ligand binding res

161 Altered splicing of CTLA-4 has been attributed to a single nucleotide polymo

162 inhibitory immune receptors PD-L1, PD-1 and CTLA-4 has emerged as a successful treatment strategy fo

163 CTLA-4 has long been associated with control of autoimmu

164 Fully human monoclonal antibodies targeting CTLA-4 have been shown to increase T cell function and a

165 Antibodies targeting CTLA-4 have been successfully used as cancer immunothera

166 tory or immune checkpoint receptors PD-1 and CTLA-4 have shown remarkable success in many cancers, no

167 The latter was largely confined to CTLA-4(hi)-expressing FOXP3(hi)-enriched CD25(hi)CD4 T c

168 lted in the induction of an effector CD69(+) CTLA-4(+) IFNAR(+) FOXP3(+) Treg subset.

169 ion was not observed in animals treated with CTLA-4 Ig (abatacept) or CD28 blockade in the presence o

170 The development of the fusion protein CTLA-4-Ig as an experimental and subsequent therapeutic

171 Blockade of CD80/CD86 with CTLA-4-Ig markedly reduced the cycling and absolute numb

172 ponses to CD28-ligand blockade by abatacept (CTLA-4-Ig) in conditions such as rheumatoid arthritis ar

173 ells that was reversed upon cotreatment with CTLA-4-Ig.

174 h the emergence of an anergic and regulatory CTLA-4(+)IL-2(low)Foxp3(-) T cell population, where the

175 PD-L1 and CTLA-4 immune checkpoints inhibit antitumour T-cell acti

176 tion therapy concurrently targeting PD-1 and CTLA-4 immune checkpoints leads to remarkable antitumor

177 el of anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4) immunotherapy of colon cancer.

178 immunocytokine, radiation, and systemic anti-CTLA-4 improved primary tumor response and animal surviv

179 a model that enables conditional deletion of CTLA-4 in adult mice, with some surprising new conclusio

180 d CD86, supporting a cell-extrinsic role for CTLA-4 in downregulating B7 ligand expression on DCs.

181 ade therapy, emphasizing the crucial role of CTLA-4 in immune checkpoint regulation.

182 amenable functional role for Treg cells and CTLA-4 in limiting antimalarial immunity.

183 nt manner, consistent with the known role of CTLA-4 in regulating the CD28 pathway.

184 e identify multifaceted regulatory roles for CTLA-4 in Tfh, Tfr, and Treg cells, which together contr

185 Targeting Treg cells or CTLA-4 in this precise window accelerated parasite clear

186 th inhibition of immune checkpoints PD-1 and CTLA-4, induced complete and durable regressions (>1 yea

187 In contrast, anti-CTLA-4 induces the expansion of an ICOS(+) Th1-like CD4

188 CTLA-4 induction following stimulation, and the use of l

189 consistent with the known safety profile of CTLA-4 inhibitors.

190 Conversely, CTLA-4 inhibits glycolysis without augmenting FAO, sugge

191 xamined the differential effects of CD28 and CTLA-4 interaction with CD80/CD86, as well as MHC class

192 ut significantly lower than that of the B7-1/CTLA-4 interaction, suggesting a distinct basis for PD-1

193 regs correlated with decreased expression of CTLA-4, interleukin-10, and transforming growth factor-b

194 atients identified as non-responders to anti-CTLA-4 (ipilimumab) have tumors with genomic defects in

195 To date, anti-CTLA-4 (ipilimumab) or anti-PD-1 (nivolumab) monotherapy

196 c CTLs followed by a standard course of anti-CTLA-4 (ipilimumab).

197 CTLA-4 is a critical "checkpoint" regulator in autoimmun

198 014) and Sage et al. (2014) demonstrate that CTLA-4 is a critical effector molecule used by regulator

199 CTLA-4 is a critical inhibitory "checkpoint" molecule of

200 Although it is clear that CTLA-4 is a critical regulator of T cell responses, the

201 intensive regimens, suggesting that blocking CTLA-4 is deleterious.

202 ce suggests that the extracellular domain of CTLA-4 is sufficient to elicit suppression.

203 Cytotoxic T lymphocyte antigen-4 (CTLA-4) is a regulatory molecule that suppresses T cell

204 Cytotoxic T lymphocyte antigen-4 (CTLA-4) is an essential negative regulator of T cell res

205 Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) is an essential regulator of T-cell responses, a

206 Variation in CTLA-4 isoform expression has been linked to type 1 diab

207 ed PD-1 with the inhibitory receptors TIM-3, CTLA-4, LAG-3, and TIGIT, but also displayed a recently

208 ibitory receptor expression patterns of 2B4, CTLA-4, LAG-3, PD-1, and Tim-3 on virus-specific CD4 and

209 nd that unlike other coinhibitory molecules (CTLA-4, LAG-3, TIM-3), PD-1 was highly expressed by subd

210 Direct mutation in CTLA-4 leads to defective regulatory T-cell (Treg) funct

211 ese individuals, their suppressive function, CTLA-4 ligand binding and transendocytosis of CD80 were

212 th impaired ability to control levels of the CTLA-4 ligands, CD80 and CD86.

213 uppressed proliferation more weakly than did CTLA-4(lo/-)CD25(hi)FOXP3(hi)-enriched T cells.

214 ecules, cytotoxic T-lymphocyte attenuator-4 (CTLA-4), lymphocyte activation gene-3 (LAG-3), and progr

215 n cells compared with mice treated with anti-CTLA-4 mAb alone.

216 Treatment with anti-CTLA-4 mAb altered MP Treg and MP CD4(+) and CD8(+) T ce

217 th other immune-modulating agents (i.e. anti-CTLA-4 mAb or anti-PD1 mAb) is particularly attractive.

218 pt) or CD28 blockade in the presence of anti-CTLA-4 mAb.

219 expressed higher levels of PD-1, TIM-3, and CTLA-4 markers of exhaustion, and (iii) produced less tu

220 suggesting a distinct basis for PD-1- versus CTLA-4-mediated inhibition.

221 these paradoxical findings in the context of CTLA-4-mediated ligand regulation.

222 nable personalized therapy with abatacept, a CTLA-4 mimetic, and inform genetic counseling.

223 exclusion and resistance to anti-PD-L1/anti-CTLA-4 monoclonal antibody therapy.

224 a T-cell inhibitory checkpoint with the anti-CTLA-4 monoclonal antibody, ipilimumab, represents a sci

225 cytotoxic-T-lymphocyte-associated antigen 4 (CTLA-4) monoclonal antibody tremelimumab in patients wit

226 ell-based binding assay against a library of CTLA-4 mutants and by direct biochemical approaches.

227 hal, making investigation of the function of CTLA-4 on mature T cells challenging.

228 To elucidate the function of CTLA-4 on mature T cells, we have conditionally ablated

229 l clear rules for the inhibitory function of CTLA-4 on regulatory T cells, which are predicted by its

230 y, our findings point to a profound role for CTLA-4 on T reg cells in limiting their peripheral expan

231 cells) T cell subsets; however, deletion of CTLA-4 on T reg cells was necessary and sufficient for p

232 In the effector phase, loss of CTLA-4 on Tfh cells resulted in heightened B cell respon

233 heightened B cell responses, whereas loss of CTLA-4 on Tfr cells resulted in defective suppression of

234 cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) on CD4(+) T cells of albendazole-treated individ

235 In contrast, induction of IDO1 using CTLA-4 or a TLR-3 ligand dampened proinflammatory respon

236 phenotypic profile in mice treated with anti-CTLA-4 or anti-PD-1 immunotherapy, whereas their periphe

237 ody modulation of T-cell coinhibitory (e.g., CTLA-4) or costimulatory (e.g., 4-1BB) receptors promote

238 cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) or PD-1/PD-L1.

239 cytotoxic T-lymphocyte-associated antigen 4 [CTLA-4] or programmed cell death 1 [PD-1]) inhibitor.

240 yping approaches sensitive to defects in the CTLA-4 pathway are therefore required to inform understa

241 Here, we focus on the biology of the CD28/CTLA-4 pathway as a framework for understanding the impa

242 s appropriate for testing novel mutations in CTLA-4 pathway genes.

243 Antibody blockade of the inhibitory CTLA-4 pathway has led to clinical benefit in a subset o

244 functional significance of mutations in the CTLA-4 pathway identified by gene-sequencing approaches.

245 Manipulation of the CD28/CTLA-4 pathway is at the heart of a number of immunomodu

246 t antagonist of CD28 that does not block the CTLA-4 pathway, and belatacept (n=5) in kidney allotrans

247 form a pathway that is analogous to the CD28/CTLA-4 pathway, in which shared ligands and differential

248 However, additional mutations affecting the CTLA-4 pathway, such as those recently reported for LRBA

249 f distinguishing a variety of defects in the CTLA-4 pathway.

250 R-424(322) regulates the PD-L1/PD-1 and CD80/CTLA-4 pathways in chemoresistant ovarian cancer.

251 contrast to PD-1(+) Tfh cells, SIV-enriched CTLA-4(+)PD-1(-) CD4(+) T cells were found outside the B

252 We have shown that CTLA-4(+)PD-1(-) memory CD4(+) T cells are a previously

253 , SIV-infected rhesus macaques, we show that CTLA-4(+)PD-1(-) memory CD4(+) T cells, which share phen

254 s of Tregs, these cells have lower levels of CTLA-4, PD-1, and CCR6, and the animals develop systemic

255 that checkpoint blockade antibodies against CTLA-4, PD-1, and PD-L1, which are used clinically, rest

256 example, using monoclonal antibodies against CTLA-4, PD-1, and PD-L1.

257 imulatory (CD28, ICOS) and inhibitory roles (CTLA-4, PD-1, BTLA, and TIGIT) in T-cell function.

258 We show that blockade of CTLA-4, PD-1, or combination of the two leads to distinc

259 ne previous systemic therapy (excluding anti-CTLA-4, PD-1, or PD-L1 agents).

260 ta-mIL12), antibodies to immune checkpoints (CTLA-4, PD-1, PD-L1), or dual combinations modestly exte

261 ngagement of inhibitory checkpoint pathways (CTLA-4, PD-1/PD-L1, LAG-3 and TIM-3), secretion of immun

262 erein, we review the clinical development of CTLA-4-, PD-1-, and PD-L1-blocking antibodies across tum

263 ll responses are controlled by both CD28 and CTLA-4/PD-L1 cosignals in vivo and that selectively targ

264 criptional inhibitor that directly bound the CTLA-4 promoter and regulated its activity.

265 tes with rather than antagonizes blockade of CTLA-4, promoting unrestrained effector function and pro

266 bined treatment with anti-CD40/CpG + IC/anti-CTLA-4 reduced T regulatory cells in the tumors and was

267 on resulted in a biased expansion of PD-1(+) CTLA-4(+) regulatory T cells (Tregs) over antiviral CD8

268 e selectivity exhibited by ipilimumab toward CTLA-4 relative to the homologous and functionally relat

269 cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) remains surprisingly unclear.

270 cytotoxic T lymphocyte-associated protein 4 (CTLA-4) restored antitumor immunity in miR-155 T cell-co

271 le combination of ISF35, anti-PD-1, and anti-CTLA-4 results in complete eradication of injected and n

272 t a combination of anti-CD40/CpG and IC/anti-CTLA-4 should be developed for clinical testing as a pot

273 cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) signalling, is associated with new-onset, immune

274 Treatment with ipilimumab, a fully human CTLA-4-specific mAb, showed durable clinical efficacy in

275 ence of irAEs compared with those that block CTLA-4 such as ipilimumab.

276 cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), such as ipilimumab, yield considerable clinical

277 ysis without augmenting FAO, suggesting that CTLA-4 sustains the metabolic profile of non-activated c

278 Anti-CD40/CpG + IC/anti-CTLA-4 synergistically induced regression of advanced s.

279 complex formed by ipilimumab with its human CTLA-4 target.

280 t typical suppressive factors such as PD-L1, CTLA-4, TGF-beta, IL-35, and IL-10, contributes to apopt

281 ilimumab is a fully human antibody targeting CTLA-4 that received FDA approval for the treatment of m

282 gene encoding the immunomodulatory receptor CTLA-4 that was associated with resistance to autoimmuni

283 the toxicities that are associated with anti-CTLA-4 therapy may differ from those of conventional the

284 Together, our results suggest that anti-CTLA-4 therapy may target Tregs in vivo.

285 naling in tumor cells in the setting of anti-CTLA-4 therapy remains unknown.

286 Animals that responded to CTLA-4 therapy showed a homogeneous distribution of the

287 s associated with primary resistance to anti-CTLA-4 therapy.

288 GR1) have impaired tumor rejection upon anti-CTLA-4 therapy.

289 umours when combined with anti-PD-1 and anti-CTLA-4 therapy.

290 Regulatory T (Treg) cells can use CTLA-4 to elicit suppression; however, CTLA-4 also opera

291 cellular location, and membrane delivery of CTLA-4 to facilitate its central function: regulating th

292 ndicate that high CD3 PET uptake in the anti-CTLA-4-treated mice correlated with subsequent reduced t

293 Our model predicts survival in anti-CTLA-4-treated patients with melanoma and anti-PD-1-trea

294 In ex vivo assays, ipilimumab targeted CTLA-4(+) Treg and restored cytolytic functions of NK ce

295 hat antibody blockade of the T cell molecule CTLA-4 unleashes the body's immune response against mali

296 ire T cells, the antitumor effect of IC/anti-CTLA-4 was dependent on T cells.

297 [PD-1] and cytotoxic T-lymphocyte antigen 4 [CTLA-4]) was similar to that of controls and cytokine ex

298 proliferative and expressed FOXP3, CD39, and CTLA-4, which are markers of functional Tregs.

299 likely through interaction with its receptor CTLA-4, which is highly expressed on skin Tregs.

300 orientated assay to measure ligand uptake by CTLA-4, which is sensitive to ligand-binding or -traffic