Akt and SHP-1 are DC-intrinsic checkpoints for tumor immunity

Carmi, Yaron; Prestwood, Tyler R.; Spitzer, Matthew H.; Linde, Ian L.; Chabon, Jonathan; Reticker-Flynn, Nathan E.; Bhattacharya, Nupur; Zhang, Hong; Zhang, Xiangyue; Basto, Pamela A.; Burt, Bryan M.; Alonso, Michael N.; Engleman, Edgar G.

doi:10.1172/jci.insight.89020

Cited by 22 publications

(19 citation statements)

References 71 publications

(74 reference statements)

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“…In order to assess the role of DC ICAMs in naïve T cell activation by migratory DCs [20] primed in the skin and entering popliteal lymph nodes, we generated in vitro BMDC, from the BM of either WT or ICAM-1 and −2 double KO (herein ICAM-1/2 DKO) mice and stimulated these antigen presenting cells with LPS 24 h prior to injection (Figure 1(a)). These BMDCs (herein referred to as ICAM-1/2 DKO BMDCs) were found to express 8-fold higher ICAM-1 and 2-fold higher MHC-II than resident adjuvant stimulated lymph node DCs but lacked surface ICAM-2 expression ( Figure 1(b), and not shown).…”

Section: Resultsmentioning

confidence: 99%

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Stable contacts of naïve CD4 T cells with migratory dendritic cells are ICAM-1-dependent but dispensable for proliferation in vivo

Kozlovski

Atrakchi

Feigelson

et al. 2019

Cell Adhesion & Migration

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It is unclear if naïve T cells require dendritic cell ICAMs to proliferate inside lymph nodes. To check if and when CD4 lymphocytes use ICAMs on migratory DCs, wild-type and ICAM-1 and 2 double knock out bone marrow-derived DCs pulsed with saturating levels of an OT-II transgene-specific ovalbumin-derived peptide were co-transferred into skin-draining lymph nodes. Intravital imaging of OT-II lymphocytes entering these lymph nodes revealed that ICAM-1 and −2 deficient migratory DCs formed fewer stable conjugates with OT-II lymphocytes but promoted normal T cell proliferation. DC ICAMs were also not required for unstable TCR-dependent lymphocyte arrests on antigen presenting migratory DCs. Thus, rare antigen-stimulated ICAM-stabilized T-DC conjugates are dispensable for CD4 lymphocyte proliferation inside lymph nodes.

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Section: Resultsmentioning

confidence: 99%

“…As a model for singular migratory DCs, we used bone marrow dendritic cells (BMDCs [18]) derived from either WT or ICAM-1 and ICAM-2 double knockout bone marrow. These DCs are extensively used in various types of vaccinations [19,20] and for dissecting DC-T cell synapses in various lymphoid organs [21][22][23].…”

Section: Introductionmentioning

confidence: 99%

Stable contacts of naïve CD4 T cells with migratory dendritic cells are ICAM-1-dependent but dispensable for proliferation in vivo

Kozlovski

Atrakchi

Feigelson

et al. 2019

Cell Adhesion & Migration

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“…A large number of studies suggest that a Th2 signature and tumor-binding antibodies promote tumor escape through various mechanisms, including masking T cell epitopes (7), inducing suppressor mechanisms (8)(9)(10)(11), inducing tumor heterogeneity and therapy resistance (12), altering the tumor microenvironment, increasing tumor proliferation, and promoting angiogenesis (13,14). In contrast, tumor-binding antibodies were shown to inhibit tumor growth through induction of antibody-dependent cell-mediated cytotoxicity (ADCC) (15), activation of DCs (16,17), and activation of tumor-infiltrating innate cells (18) and were shown to be required for antitumor T cell activity (19,20). In the clinic, tumor-binding antibodies are widely used as therapeutic agents (21), and when they arise spontaneously, they correlate with a positive prognosis in several cancers (22,23).…”

Section: Introductionmentioning

confidence: 99%

“…By studying spontaneous regression of tumor cells in genetically similar allogeneic hosts (MHC-I and -II matched), we discovered that naturally occurring IgG antibodies enable tumor-associated DCs (TADCs) to activate T cells that recognize a wide range of tumor-associated antigens, including neoantigens (28). Through exploiting this principle, we were able to generate a very potent immunotherapy consisting of a combination of tumor-binding antibodies and DC stimuli (16,28). Despite eliciting a strong T cell immune response, in this as well as in most immunotherapeutic approaches to cancer, most tumors eventually relapse, probably as a result of intratumor heterogenicity and the capacity of tumors to escape immune pressure by editing the antigens that they express.…”

Section: Introductionmentioning

confidence: 99%

A distinct subset of FcγRI-expressing Th1 cells exert antibody-mediated cytotoxic activity

Rasoulouniriana¹,

Santana-Magal²,

Gutwillig³

et al. 2019

Journal of Clinical Investigation

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We recently found that treating tumor-bearing mice with tumorbinding antibodies and DC stimuli induces complete tumor regression through induction of systemic T cell immunity (16, 28). This treatment, however, is limited to tumors smaller than 25 mm 2 and is largely ineffective once tumors exceed that size. In attempts While a high frequency of Th1 cells in tumors is associated with improved cancer prognosis, this benefit has been attributed mainly to support of cytotoxic activity of CD8 + T cells. By attempting to potentiate antibody-driven immunity, we found a remarkable synergy between CD4 + T cells and tumor-binding antibodies. This surprising synergy was mediated by a small subset of tumor-infiltrating CD4 + T cells that express the high-affinity Fcγ receptor for IgG (FcγRI) in both mouse and human patients. These cells efficiently lyse tumor cells coated with antibodies through concomitant crosslinking of their T cell receptor (TCR) and FcγRI. By expressing FcγRI and its signaling chain in conventional CD4 + T cells, we successfully employed this mechanism to treat established solid cancers. Overall, this discovery sheds new light on the biology of this T cell subset, their function during tumor immunity, and the means to utilize their unique killing signals in immunotherapy.

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“…Thus, activation of humoral responses within TLS can improve responses, particularly in the context of immunotherapy ( Germain et al, 2014 ; Helmink et al, 2020 ; Montfort et al, 2017 ; Sautès-Fridman et al, 2016 ; Cottrell et al, 2018 ; Sautès-Fridman et al, 2019 ). Furthermore, while FcR binding of tumor-immune complexes has been suggested to promote tumor progression ( Andreu et al, 2010 ), we have found that combining tumor-binding antibodies with DC adjuvants and CD40 agonists results in extremely potent anti-tumor responses in a manner that is FcR-dependent ( Spitzer et al, 2017 ; Carmi et al, 2015 ; Carmi et al, 2016 ).…”

Section: Systems Approaches To Understanding the Roles Of Specific Immentioning

confidence: 99%

Cancer systems immunology

Reticker-Flynn

Engleman

2020

eLife

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Tumor immunology is undergoing a renaissance due to the recent profound clinical successes of tumor immunotherapy. These advances have coincided with an exponential growth in the development of –omics technologies. Armed with these technologies and their associated computational and modeling toolsets, systems biologists have turned their attention to tumor immunology in an effort to understand the precise nature and consequences of interactions between tumors and the immune system. Such interactions are inherently multivariate, spanning multiple time and size scales, cell types, and organ systems, rendering systems biology approaches particularly amenable to their interrogation. While in its infancy, the field of ‘Cancer Systems Immunology’ has already influenced our understanding of tumor immunology and immunotherapy. As the field matures, studies will move beyond descriptive characterizations toward functional investigations of the emergent behavior that govern tumor-immune responses. Thus, Cancer Systems Immunology holds incredible promise to advance our ability to fight this disease.

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Akt and SHP-1 are DC-intrinsic checkpoints for tumor immunity

Cited by 22 publications

References 71 publications

Stable contacts of naïve CD4 T cells with migratory dendritic cells are ICAM-1-dependent but dispensable for proliferation in vivo

Stable contacts of naïve CD4 T cells with migratory dendritic cells are ICAM-1-dependent but dispensable for proliferation in vivo

A distinct subset of FcγRI-expressing Th1 cells exert antibody-mediated cytotoxic activity

Cancer systems immunology

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