Modulation of T cell responses by myeloid cells isolated from mice with active colitis

ABSTRACT The gastric bacterium Helicobacter pylori causes a persistent infection that is directly responsible for gastric ulcers and gastric cancer in some patients and protective against allergic and other immunological disorders in others. The two outcomes of the Helicobacter-host interaction can be modeled in mice that are infected as immunocompetent adults and as neonates, respectively. Here, we have investigated the contribution of the Helicobacter immunomodulator VacA to H. pylori-specific local and systemic immune responses in both models. We found that neonatally infected mice are colonized at higher levels than mice infected as adults and fail to generate effector T-cell responses to the bacteria; rather, T-cell responses in neonatally infected mice are skewed toward Foxp3-positive (Foxp3+) regulatory T cells that are neuropilin negative and express RORγt. We found these peripherally induced regulatory T cells (pTregs) to be enriched, in a VacA-dependent manner, not only in the gastric mucosa but also in the lungs of infected mice. Pulmonary pTreg accumulation was observed in mice that have been infected neonatally with wild-type H. pylori but not in mice that have been infected as adults or mice infected with a VacA null mutant. Finally, we traced VacA to gastric lamina propria myeloid cells and show that it suppressed interleukin-23 (IL-23) expression by dendritic cells and induced IL-10 and TGF-β expression in macrophages. Taken together, the results are consistent with the idea that H. pylori creates a tolerogenic environment through its immunomodulator VacA, which skews T-cell responses toward Tregs, favors H. pylori persistence, and affects immunity at distant sites. IMPORTANCE Helicobacter pylori has coexisted with humans for at least 60.000 years and has evolved persistence strategies that allow it to evade host immunity and colonize its host for life. The VacA protein is expressed by all H. pylori strains and is required for high-level persistent infection in experimental mouse models. Here, we show that VacA targets myeloid cells in the gastric mucosa to create a tolerogenic environment that facilitates regulatory T-cell differentiation, while suppressing effector T-cell priming and functionality. Tregs that are induced in the periphery during H. pylori infection can be found not only in the stomach but also in the lungs of infected mice, where they are likely to affect immune responses to allergens.

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Vaccination during myeloid cell depletion by cancer chemotherapy fosters robust T cell responses

Science Translational Medicine ◽

10.1126/scitranslmed.aad8307 ◽

2016 ◽

Vol 8 (334) ◽

pp. 334ra52-334ra52 ◽

Cited By ~ 89

Author(s):

Marij J. Welters ◽

Tetje C. van der Sluis ◽

Hélène van Meir ◽

Nikki M. Loof ◽

Vanessa J. van Ham ◽

...

Keyword(s):

Cervical Cancer ◽

T Cell ◽

Myeloid Cells ◽

Myeloid Cell ◽

T Cell Responses ◽

Mouse Tumor ◽

Therapeutic Vaccination ◽

Advanced Cervical Cancer ◽

Hpv16 E6 ◽

Cell Responses

Therapeutic vaccination with human papillomavirus type 16 synthetic long peptides (HPV16-SLPs) results in T cell–mediated regression of HPV16-induced premalignant lesions but fails to install clinically effective immunity in patients with HPV16-positive cervical cancer. We explored whether HPV16-SLP vaccination can be combined with standard carboplatin and paclitaxel chemotherapy to improve immunity and which time point would be optimal for vaccination. This was studied in the HPV16 E6/E7–positive TC-1 mouse tumor model and in patients with advanced cervical cancer. In mice and patients, the presence of a progressing tumor was associated with abnormal frequencies of circulating myeloid cells. Treatment of TC-1–bearing mice with chemotherapy and therapeutic vaccination resulted in superior survival and was directly related to a chemotherapy-mediated altered composition of the myeloid cell population in the blood and tumor. Chemotherapy had no effect on tumor-specific T cell responses. In advanced cervical cancer patients, carboplatin-paclitaxel also normalized the abnormal numbers of circulating myeloid cells, and this was associated with increased T cell reactivity to recall antigens. The effect was most pronounced starting 2 weeks after the second cycle of chemotherapy, providing an optimal immunological window for vaccination. This was validated with a single dose of HPV16-SLP vaccine given in this time window. The resulting proliferative HPV16-specific T cell responses were unusually strong and were retained after all cycles of chemotherapy. In conclusion, carboplatin-paclitaxel therapy fosters vigorous vaccine-induced T cell responses when vaccination is given after chemotherapy and has reset the tumor-induced abnormal myeloid cell composition to normal values.

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Myeloid-Derived Suppressor Cells (MDSCs) in Haematology

Journal of Clinical Medicine ◽

10.3390/jcm11010187 ◽

2021 ◽

Vol 11 (1) ◽

pp. 187

Author(s):

Nikoleta Bizymi ◽

Helen A. Papadaki

Keyword(s):

T Cell ◽

Myeloid Cells ◽

Suppressor Cells ◽

T Cell Responses ◽

Myeloid Derived Suppressor Cells ◽

Cell Responses ◽

Immature Myeloid Cells

Myeloid-derived suppressor cells (MDSCs) are immature myeloid cells with immunomodulating properties, mainly acting by suppressing T-cell responses [...]

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Arginase I Production in the Tumor Microenvironment by Mature Myeloid Cells Inhibits T-Cell Receptor Expression and Antigen-Specific T-Cell Responses

Cancer Research ◽

10.1158/0008-5472.can-04-0465 ◽

2004 ◽

Vol 64 (16) ◽

pp. 5839-5849 ◽

Cited By ~ 626

Author(s):

Paulo C. Rodriguez ◽

David G. Quiceno ◽

Jovanny Zabaleta ◽

Blair Ortiz ◽

Arnold H. Zea ◽

...

Keyword(s):

T Cell ◽

Tumor Microenvironment ◽

T Cell Receptor ◽

Myeloid Cells ◽

T Cell Responses ◽

Cell Receptor ◽

Receptor Expression ◽

Cell Responses ◽

Arginase I

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Mild SARS-CoV-2 infection in rhesus macaques is associated with viral control prior to antigen-specific T cell responses in tissues

10.1101/2022.01.06.475282 ◽

2022 ◽

Author(s):

Christine E. Nelson ◽

Sivaranjani Namasivayam ◽

Taylor W. Foreman ◽

Keith D. Kauffman ◽

Shunsuke Sakai ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Immune Responses ◽

Post Infection ◽

Rhesus Macaques ◽

Myeloid Cells ◽

T Cell Responses ◽

Viral Rna ◽

Viral Control ◽

Cell Responses

SARS-CoV-2 primarily replicates in mucosal sites, and more information is needed about immune responses in infected tissues. We used rhesus macaques to model protective primary immune responses in tissues during mild COVID-19. Viral RNA levels were highest on days 1-2 post-infection and fell precipitously thereafter. 18F-fluorodeoxyglucose (FDG)-avid lung abnormalities and interferon (IFN)-activated myeloid cells in the bronchoalveolar lavage (BAL) were found on days ~3-4. Virus-specific effector CD8 and CD4 T cells were detectable in the BAL and lung tissue on days ~7-10, after viral RNA, lung inflammation, and IFN-activated myeloid cells had declined. Notably, SARS-CoV-2-specific T cells were not detectable in the nasal turbinates, salivary glands, and tonsils on day 10 post-infection. Thus, SARS-CoV-2 replication wanes in the lungs prior to T cell responses, and in the nasal and oral mucosa despite the apparent lack of Ag-specific T cells, suggesting that innate immunity efficiently restricts viral replication during mild COVID-19.

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Human B7-H3 binds to Triggering receptor expressed on myeloid cells-like transcript 2 (TLT-2) and enhances T cell responses

Open Journal of Immunology ◽

10.4236/oji.2012.21002 ◽

2012 ◽

Vol 02 (01) ◽

pp. 9-16 ◽

Cited By ~ 5

Author(s):

Masaaki Hashiguchi ◽

Yuka Inamochi ◽

Shoya Nagai ◽

Noriko Otsuki ◽

Jinhua Piao ◽

...

Keyword(s):

T Cell ◽

Myeloid Cells ◽

T Cell Responses ◽

Cell Responses

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Immunosuppressive Myeloid Cells Induced by Chemotherapy Attenuate Antitumor CD4+ T-Cell Responses through the PD-1–PD-L1 Axis

Cancer Research ◽

10.1158/0008-5472.can-13-3596 ◽

2014 ◽

Vol 74 (13) ◽

pp. 3441-3453 ◽

Cited By ~ 74

Author(s):

Zhi-Chun Ding ◽

Xiaoyun Lu ◽

Miao Yu ◽

Henrique Lemos ◽

Lei Huang ◽

...

Keyword(s):

T Cell ◽

Myeloid Cells ◽

T Cell Responses ◽

Cd4 T Cell ◽

Cell Responses

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393 A phase 1/2 study of SBT6050 combined with trastuzumab deruxtecan (T-DXd) or trastuzumab and tucatinib with or without capecitabine in patients with HER2-expressing or HER2-amplified cancers

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2021-sitc2021.393 ◽

2021 ◽

Vol 9 (Suppl 3) ◽

pp. A426-A426

Author(s):

Samuel Klempner ◽

John Strickler ◽

Lindsey Gourley ◽

Celine Jacquemont ◽

Vinona Bhatia ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Phase 1 ◽

Single Agent ◽

Myeloid Cells ◽

T Cell Responses ◽

Human Tumor Xenograft ◽

Tumor Cell Death ◽

Her2 Positive ◽

Cell Responses

BackgroundSBT6050 is a novel therapeutic comprising a selective small molecule toll-like receptor 8 (TLR8) agonist linked to the HER2-directed monoclonal antibody pertuzumab, allowing for combination with trastuzumab-based agents and regimens. SBT6050 is designed to activate myeloid cells in tumors expressing moderate to high levels of HER2. TLR8 agonism directly activates myeloid cells, including macrophages and dendritic cells (DCs), and secondarily activates NK and T cells, inducing a broad spectrum of anti-tumor immune mechanisms. SBT6050 is currently being tested as a single agent and in combination with checkpoint inhibitors (NCT04460456). Initial results show early evidence of anti-tumor effects, activation of myeloid and NK/T cells, and a safety profile consistent with an immune activator that is generally non-overlapping with that of T-DXd or tucatinib-based regimens.A strong scientific rationale supports the combination of SBT6050 with T-DXd and SBT6050 with trastuzumab and tucatinib ± capecitabine. Both treatment regimens drive tumor cell death and release of tumor neoantigens. SBT6050 can enhance tumor neoantigen presentation and subsequent activation of T cell responses through its direct activation of DCs. SBT6050 combined with T-DXd or trastuzumab and tucatinib ± capecitabine is postulated to drive increased anti-tumor T cell responses. In addition, T-DXd and trastuzumab support antibody-dependent cell mediated cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) and SBT6050 can enhance both functions. SBT6050 activates myeloid cells to secrete cytokines that amplify ADCC by NK cells. Additionally, SBT6050 activation downmodulates SIRPα on the surface of myeloid cells which can increase ADCP through attenuation of the CD47-SIRPα interaction. Consistent with this mechanism of action, in preclinical studies in mice, the combination of trastuzumab and a mouse surrogate of SBT6050 led to enhanced activity in the HER2-positive NCI-N87 human tumor xenograft model compared to either agent alone.MethodsProtocol SBT6050-201 is a phase 1/2, open-label, dose-escalation and expansion study evaluating SBT6050 in combination with either T-DXd (Part 1) or tucatinib and trastuzumab +/- capecitabine (Part 2). Eligible patients are at least 18 years old, have HER2-positive metastatic breast cancer, gastric/GEJ cancer, colorectal cancer, or HER2-expressing or amplified NSCLC, and have received at least one prior therapy for metastatic disease. Patients will receive SBT6050 subcutaneously q3wk starting at a dose with demonstrated pharmacodynamic activity in phase 1. Pharmacodynamic markers of myeloid and NK/T cell activation will be assessed in peripheral blood and on-treatment tumor biopsies. Circulating tumor DNA will be evaluated as an exploratory assessment.Ethics ApprovalThis clinical study has not yet obtained ethics approval or started enrollment. All participants will be required to give informed consent before taking part.

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