Vaccination during myeloid cell depletion by cancer chemotherapy fosters robust T 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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Innate cell microenvironments in lymph nodes shape the generation of T cell responses during type I inflammation

Science Immunology ◽

10.1126/sciimmunol.abb9435 ◽

2021 ◽

Vol 6 (56) ◽

pp. eabb9435

Author(s):

Joseph M. Leal ◽

Jessica Y. Huang ◽

Karan Kohli ◽

Caleb Stoltzfus ◽

Miranda R. Lyons-Cohen ◽

...

Keyword(s):

T Cell ◽

Immune Responses ◽

Lymph Nodes ◽

Critical Role ◽

Myeloid Cell ◽

T Cell Responses ◽

Type I ◽

Cell Responses ◽

Inflammatory Monocytes ◽

Cell Effector

Microanatomical organization of innate immune cells within lymph nodes (LNs) is critical for the generation of adaptive responses. In particular, steady-state LN-resident dendritic cells (Res cDCs) are strategically localized to intercept lymph-draining antigens. Whether myeloid cell organization changes during inflammation and how that might affect the generation of immune responses are unknown. Here, we report that during type I, but not type II, inflammation after adjuvant immunization or viral infection, antigen-presenting Res cDCs undergo CCR7-dependent intranodal repositioning from the LN periphery into the T cell zone (TZ) to elicit T cell priming. Concurrently, inflammatory monocytes infiltrate the LNs via local blood vessels, enter the TZ, and cooperate with Res cDCs by providing polarizing cytokines to optimize T cell effector differentiation. Monocyte infiltration is nonuniform across LNs, generating distinct microenvironments with varied local innate cell composition. These spatial microdomains are associated with divergent early T cell effector programming, indicating that innate microenvironments within LNs play a critical role in regulating the quality and heterogeneity of T cell responses. Together, our findings reveal that dynamic modulation of innate cell microenvironments during type I inflammation leads to optimized generation of adaptive immune responses to vaccines and infections.

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Human Papillomavirus Type 16 E7 Peptide-Directed CD8+ T Cells from Patients with Cervical Cancer Are Cross-Reactive with the Coronavirus NS2 Protein

Journal of Virology ◽

10.1128/jvi.77.9.5464-5474.2003 ◽

2003 ◽

Vol 77 (9) ◽

pp. 5464-5474 ◽

Cited By ~ 53

Author(s):

Katja Nilges ◽

Hanni Höhn ◽

Henryk Pilch ◽

Claudia Neukirch ◽

Kirsten Freitag ◽

...

Keyword(s):

Cervical Cancer ◽

Immune Response ◽

T Cells ◽

Human Papillomavirus ◽

T Cell ◽

T Cell Responses ◽

Cross Reactivity ◽

Antiviral Immune Response ◽

Human Papillomavirus Type 16 ◽

Cell Responses

ABSTRACT Human papillomavirus type 16 (HPV16) E6 and E7 oncoproteins are required for cellular transformation and represent candidate targets for HPV-specific and major histocompatibility complex class I-restricted CD8+-T-cell responses in patients with cervical cancer. Recent evidence suggests that cross-reactivity represents the inherent nature of the T-cell repertoire. We identified HLA-A2 binding HPV16 E7 variant peptides from human, bacterial, or viral origin which are able to drive CD8+-T-cell responses directed against wild-type HPV16 E7 amino acid 11 to 19/20 (E711-19/20) epitope YMLDLQPET(T) in vitro. CD8+ T cells reacting to the HLA-A2-presented peptide from HPV16 E711-19(20) recognized also the HLA-A2 binding peptide TMLDIQPED (amino acids 52 to 60) from the human coronavirus OC43 NS2 gene product. Establishment of coronavirus NS2-specific, HLA-A2-restricted CD8+-T-cell clones and ex vivo analysis of HPV16 E7 specific T cells obtained by HLA-A2 tetramer-guided sorting from PBL or tumor-infiltrating lymphocytes obtained from patients with cervical cancer showed that cross-reactivity with HPV16 E711-19(20) and coronavirus NS252-60 represents a common feature of this antiviral immune response defined by cytokine production. Zero of 10 patients with carcinoma in situ neoplasia and 3 of 18 patients with cervical cancer showed ≥0.1% HPV16 E7-reactive T cells in CD8+ peripheral blood lymphocytes. In vivo priming with HPV16 was confirmed in patients with cervical cancer or preinvasive HPV16-positive lesions using HLA-A2 tetramer complexes loaded with the E6-derived epitope KLPQLCTEL. In contrast, we could not detect E6-reactive T cells in healthy individuals. These data imply that the measurement of the HPV16 E711-19(20) CD8+-T-cell response may reflect cross-reactivity with a common pathogen and that variant peptides may be employed to drive an effective cellular immune response against HPV.

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Corrigendum to ‘Therapeutic vaccination refocuses T-cell responses towards conserved regions of HIV-1 in early treated individuals (BCN 01 study)’ EClinicalMedicine 11 (2019) 65–80

EClinicalMedicine ◽

10.1016/j.eclinm.2019.100250 ◽

2020 ◽

Vol 18 ◽

pp. 100250

Author(s):

Beatriz Mothe ◽

Christian Manzardo ◽

Alvaro Sanchez-Bernabeu ◽

Pep Coll ◽

Sara Morón-López ◽

...

Keyword(s):

T Cell ◽

T Cell Responses ◽

Therapeutic Vaccination ◽

Cell Responses ◽

Conserved Regions ◽

Hiv 1

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Helicobacter pylori VacA Targets Myeloid Cells in the Gastric Lamina Propria To Promote Peripherally Induced Regulatory T-Cell Differentiation and Persistent Infection

mBio ◽

10.1128/mbio.00261-19 ◽

2019 ◽

Vol 10 (2) ◽

Cited By ~ 9

Author(s):

Aleksandra Altobelli ◽

Michael Bauer ◽

Karelia Velez ◽

Timothy L. Cover ◽

Anne Müller

Keyword(s):

Helicobacter Pylori ◽

T Cell ◽

Persistent Infection ◽

Myeloid Cells ◽

T Cell Responses ◽

T Cell Differentiation ◽

Content Type ◽

Effector T Cell ◽

Cell Responses ◽

H Pylori

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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Therapeutic Vaccination Refocuses T-cell Responses Towards Conserved Regions of HIV-1 in Early Treated Individuals (BCN 01 study)

EClinicalMedicine ◽

10.1016/j.eclinm.2019.05.009 ◽

2019 ◽

Vol 11 ◽

pp. 65-80 ◽

Cited By ~ 19

Author(s):

Beatriz Mothe ◽

Christian Manzardo ◽

Alvaro Sanchez-Bernabeu ◽

Pep Coll ◽

Sara Morón-López ◽

...

Keyword(s):

T Cell ◽

T Cell Responses ◽

Therapeutic Vaccination ◽

Cell Responses ◽

Conserved Regions ◽

Hiv 1

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Intramuscular Therapeutic Vaccination Targeting HPV16 Induces T Cell Responses That Localize in Mucosal Lesions

Science Translational Medicine ◽

10.1126/scitranslmed.3007323 ◽

2014 ◽

Vol 6 (221) ◽

pp. 221ra13-221ra13 ◽

Cited By ~ 109

Author(s):

L. Maldonado ◽

J. E. Teague ◽

M. P. Morrow ◽

I. Jotova ◽

T. C. Wu ◽

...

Keyword(s):

T Cell ◽

T Cell Responses ◽

Therapeutic Vaccination ◽

Cell Responses ◽

Mucosal Lesions

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

Inflammatory Bowel Diseases ◽

10.1097/00054725-201112002-00218 ◽

2011 ◽

Vol 17 ◽

pp. S67-S68

Author(s):

Dmitry Ostanin ◽

Elvira Kurmaeva ◽

Seth Berney

Keyword(s):

T Cell ◽

Myeloid Cells ◽

T Cell Responses ◽

Cell Responses ◽

Active Colitis

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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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Correlation between strength of T-cell response against HPV16 and survival after vaccination with HPV16 long peptides in combination with chemotherapy for late-stage cervical cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.7_suppl.140 ◽

2017 ◽

Vol 35 (7_suppl) ◽

pp. 140-140 ◽

Cited By ~ 3

Author(s):

Cornelis Joseph Melief ◽

Winald R. Gerritsen ◽

Marij Welters ◽

Ignace Vergote ◽

Judith R. Kroep ◽

...

Keyword(s):

Cervical Cancer ◽

T Cell ◽

Late Stage ◽

Cell Response ◽

T Cell Responses ◽

T Cell Response ◽

Premalignant Lesions ◽

Cell Responses ◽

Number Of Patients ◽

Synthetic Long Peptides

140 Background: Therapeutic vaccination with HPV type 16 synthetic long peptides (HPV16-SLP) results in T cell–mediated regression of HPV16-induced premalignant lesions but fails to install effective immunity in patients with advanced HPV16-positive cervical cancer. We showed that HPV16-SLP vaccination in mice and in patients with advanced cervical cancer patients fosters robust HPV16-specific T cell responses, when combined with chemotherapy. In this study we noted that a single dose of vaccine 2 weeks into the 2nd cycle of chemotherapy was optimal, because at this time the immunosuppressive myeloid cells were down. Methods: We now completed a chemo-immunotherapy study in a larger number of patients with late stage HPV16+ cervical cancer. Three HPV16-SLP vaccine doses were given 2 weeks after the second, third, and fourth cycles of standard chemotherapy. Cohorts of 12 patients each were vaccinated with each of 4 dose levels (20, 40, 100, and 300 µg/ per peptide) of 13 overlapping HPV16 synthetic long peptides (HPV16-SLP) together covering the length of the 2 E6 and E7 proteins. Results: Robust vaccine-induced HPV16-specific T cell responses as assessed by interferon-g Elispot were observed and were sustained throughout the cycles of chemotherapy. These T cell responses were substantially increased in all patients who received HPV16-SLP . In addition, the chemotherapy augmented recall responses to microbial antigens. Such robust T cell responses were not noted in previous trials when similar patients were vaccinated without timing of vaccination during chemotherapy. A marked correlation was observed between the strength of the vaccine-induced immune response and longer-term clinical outcomes such as overall survival. No such correlation exists between the strength of the T cell response against common recall antigens and survival. In addition, a remarkably high proportion of patients survived beyond 20 months after the start of therapy. Conclusions: These results indicate that the survival advantage is specifically related to the strength of the vaccine-induced T cell response and is not due to generally better immuno-competence. Clinical trial information: NCT02128126.

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