Clonal Abundance of Tumor-Specific CD4 + T Cells Potentiates Efficacy and Alters Susceptibility to Exhaustion

Malandro, Nicole; Budhu, Sadna; Kuhn, Nicholas F.; Liu, Cailian; Murphy, Judith T.; Cortez, Czrina; Zhong, Hong; Yang, Xia; Rizzuto, Gabrielle; Altan‐Bonnet, Grégoire; Merghoub, Taha; Wolchok, Jedd D.

doi:10.1016/j.immuni.2015.12.018

Cited by 44 publications

(31 citation statements)

References 43 publications

(49 reference statements)

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“…Instead, decreased melanoma growth with Aire deficiency and CTLA-4 blockade was associated with increased intratumoral CD4 + T cell KLRG1 expression and cytolytic protein expression. These findings add to recent reports that CD4 + T cells have direct antitumor effects, especially if clonally expanded (22,40), and that aCTLA-4 antibody treatment activates tumor-reactive cytotoxic CD4 + T cells (41). CTLA-4 blockade is associated with colitis and other immune-related adverse events (2,28).…”

Section: Discussionsupporting

confidence: 74%

Combination central tolerance and peripheral checkpoint blockade unleashes antimelanoma immunity

Bakhru¹,

Zhu²,

Wang³

et al. 2017

JCI Insight

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Section: Discussionsupporting

confidence: 74%

Combination central tolerance and peripheral checkpoint blockade unleashes antimelanoma immunity

Bakhru¹,

Zhu²,

Wang³

et al. 2017

JCI Insight

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“…Our data suggest that this tumor recognition bias of Treg may be exploited by approaches that induce Treg conversion into MHC class II/peptide-reactive effector cells that directly kill tumor cells (21)(22)(23). These considerations suggest that protocols for transfer of TAA-specific CD4 T cells may benefit from approaches that down-regulate Helios expression by CD4 Tregs to obtain increased antitumor reactivity from both conventional CD4 cells and Helios-deficient converted Tregs.…”

Section: Discussionmentioning

confidence: 89%

Instability of Helios-deficient Tregs is associated with conversion to a T-effector phenotype and enhanced antitumor immunity

Nakagawa

Sido

Reyes

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

144

135

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Expression of the transcription factor Helios by Tregs ensures stable expression of a suppressive and anergic phenotype in the face of intense inflammatory responses, whereas Helios-deficient Tregs display diminished lineage stability, reduced FoxP3 expression, and production of proinflammatory cytokines. Here we report that selective Helios deficiency within CD4 Tregs leads to enhanced antitumor immunity through induction of an unstable phenotype and conversion of intratumoral Tregs into T effector cells within the tumor microenvironment. Induction of an unstable Treg phenotype is associated with enhanced production of proinflammatory cytokines by tumor-infiltrating but not systemic Tregs and significantly delayed tumor growth. Ab-dependent engagement of Treg surface receptors that result in Helios down-regulation also promotes conversion of intratumoral but not systemic Tregs into T effector cells and leads to enhanced antitumor immunity. These findings suggest that selective instability and conversion of intratumoral CD4 Tregs through genetic or Ab-based targeting of Helios may represent an effective approach to immunotherapy.inflammation | tumor microenvironment | effector cytokines |

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“…S7, D and E). This polyfunctional effector T cell phenotype has previously been shown to elicit a potent antitumor response (25). …”

Section: Resultsmentioning

confidence: 99%

Combined immune checkpoint blockade as a therapeutic strategy for BRCA1 -mutated breast cancer

et al. 2017

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Immune checkpoint inhibitors have emerged as a potent new class of anticancer therapy. They have changed the treatment landscape for a range of tumors, particularly those with a high mutational load. To date, however, modest results have been observed in breast cancer, where tumors are rarely hypermutated. Because BRCA1-associated tumors frequently exhibit a triple-negative phenotype with extensive lymphocyte infiltration, we explored their mutational load, immune profile, and response to checkpoint inhibition in a Brca1-deficient tumor model. BRCA1-mutated triple-negative breast cancers (TNBCs) exhibited an increased somatic mutational load and greater numbers of tumor-infiltrating lymphocytes, with increased expression of immunomodulatory genes including PDCD1 (PD-1) and CTLA4, when compared to TNBCs from BRCA1–wild-type patients. Cisplatin treatment combined with dual anti–programmed death-1 and anti–cytotoxic T lymphocyte–associated antigen 4 therapy substantially augmented antitumor immunity in Brca1-deficient mice, resulting in an avid systemic and intratumoral immune response. This response involved enhanced dendritic cell activation, reduced suppressive FOXP3+ regulatory T cells, and concomitant increase in the activation of tumor-infiltrating cytotoxic CD8+ and CD4+ T cells, characterized by the induction of polyfunctional cytokine-producing T cells. Dual (but not single) checkpoint blockade together with cisplatin profoundly attenuated the growth of Brca1-deficient tumors in vivo and improved survival. These findings provide a rationale for clinical studies of combined immune checkpoint blockade in BRCA1-associated TNBC.

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Clonal Abundance of Tumor-Specific CD4 + T Cells Potentiates Efficacy and Alters Susceptibility to Exhaustion

Cited by 44 publications

References 43 publications

Combination central tolerance and peripheral checkpoint blockade unleashes antimelanoma immunity

Combination central tolerance and peripheral checkpoint blockade unleashes antimelanoma immunity

Instability of Helios-deficient Tregs is associated with conversion to a T-effector phenotype and enhanced antitumor immunity

Combined immune checkpoint blockade as a therapeutic strategy for BRCA1 -mutated breast cancer

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