Therapeutic activation of virus-specific resident memory T cells within the glioblastoma microenvironment

Glioblastoma multiforme (GBM) is among the most aggressive, treatment resistant cancers, and despite standard of care surgery, radiation and chemotherapy, is invariably fatal. GBM is marked by local and systemic immunosuppression, contributing to resistance to existing immunotherapies that have had success in other tumor types. Memory T cells specific for previous infections reside in tissues throughout the host and these tissue resident memory T cells (TRM) are capable of rapid and potent immune activation. Here, we show that virus-specific memory CD8+ T cells expressing tissue resident markers populate mouse and human glioblastoma microenvironment. Reactivating virus-specific TRM through intra-tumoral delivery of adjuvant-free virus-derived peptide triggered local immune activation. This delivery translated to anti-neoplastic effects, which improved survival in a murine glioblastoma model. Our results indicate that virus-specific TRM are a significant part of the glioblastoma immune microenvironment and can be leveraged to promote anti-tumoral immunity.

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CXCR6 regulates localization of tissue-resident memory CD8 T cells to the airways

Journal of Experimental Medicine ◽

10.1084/jem.20181308 ◽

2019 ◽

Vol 216 (12) ◽

pp. 2748-2762 ◽

Cited By ~ 35

Author(s):

Alexander N. Wein ◽

Sean R. McMaster ◽

Shiki Takamura ◽

Paul R. Dunbar ◽

Emily K. Cartwright ◽

...

Keyword(s):

T Cells ◽

Cd8 T Cells ◽

Protective Immunity ◽

Memory T Cells ◽

Respiratory Pathogens ◽

First Line ◽

Memory Cd8 T Cells ◽

Effector Functions ◽

Signaling Axis ◽

Resident Memory T Cells

Resident memory T cells (TRM cells) are an important first-line defense against respiratory pathogens, but the unique contributions of lung TRM cell populations to protective immunity and the factors that govern their localization to different compartments of the lung are not well understood. Here, we show that airway and interstitial TRM cells have distinct effector functions and that CXCR6 controls the partitioning of TRM cells within the lung by recruiting CD8 TRM cells to the airways. The absence of CXCR6 significantly decreases airway CD8 TRM cells due to altered trafficking of CXCR6−/− cells within the lung, and not decreased survival in the airways. CXCL16, the ligand for CXCR6, is localized primarily at the respiratory epithelium, and mice lacking CXCL16 also had decreased CD8 TRM cells in the airways. Finally, blocking CXCL16 inhibited the steady-state maintenance of airway TRM cells. Thus, the CXCR6/CXCL16 signaling axis controls the localization of TRM cells to different compartments of the lung and maintains airway TRM cells.

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Circulating memory CD8 + T cells are limited in forming CD103 + tissue‐resident memory T cells at mucosal sites after reinfection

European Journal of Immunology ◽

10.1002/eji.202048737 ◽

2020 ◽

Author(s):

Felix M. Behr ◽

Ammarina Beumer‐Chuwonpad ◽

Natasja A. M. Kragten ◽

Thomas H. Wesselink ◽

Regina Stark ◽

...

Keyword(s):

T Cells ◽

Cd8 T Cells ◽

Memory T Cells ◽

Memory Cd8 T Cells ◽

Resident Memory T Cells

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Mucosal delivery of a multistage subunit vaccine promotes development of lung-resident memory T cells and affords interleukin-17-dependent protection against pulmonary tuberculosis

npj Vaccines ◽

10.1038/s41541-020-00255-7 ◽

2020 ◽

Vol 5 (1) ◽

Author(s):

Claudio Counoupas ◽

Kia C. Ferrell ◽

Anneliese Ashhurst ◽

Nayan D. Bhattacharyya ◽

Gayathri Nagalingam ◽

...

Keyword(s):

T Cells ◽

Memory T Cells ◽

T Cell Subsets ◽

Interleukin 17 ◽

Intratracheal Administration ◽

Tlr9 Agonist ◽

Parenteral Delivery ◽

Specific Memory ◽

Vaccine Approach ◽

Resident Memory T Cells

AbstractThe development of effective vaccines against bacterial lung infections requires the induction of protective, pathogen-specific immune responses without deleterious inflammation within the pulmonary environment. Here, we made use of a polysaccharide-adjuvanted vaccine approach to elicit resident pulmonary T cells to protect against aerosol Mycobacterium tuberculosis infection. Intratracheal administration of the multistage fusion protein CysVac2 and the delta-inulin adjuvant Advax™ (formulated with a TLR9 agonist) provided superior protection against aerosol M. tuberculosis infection in mice, compared to parenteral delivery. Surprisingly, removal of the TLR9 agonist did not impact vaccine protection despite a reduction in cytokine-secreting T cell subsets, particularly CD4+IFN-γ+IL-2+TNF+ multifunctional T cells. CysVac2/Advax-mediated protection was associated with the induction of lung-resident, antigen-specific memory CD4+ T cells that expressed IL-17 and RORγT, the master transcriptional regulator of Th17 differentiation. IL-17 was identified as a key mediator of vaccine efficacy, with blocking of IL-17 during M. tuberculosis challenge reducing phagocyte influx, suppressing priming of pathogen-specific CD4+ T cells in local lymph nodes and ablating vaccine-induced protection. These findings suggest that tuberculosis vaccines such as CysVac2/Advax that are capable of eliciting Th17 lung-resident memory T cells are promising candidates for progression to human trials.

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Skin-resident memory CD8+ T cells trigger a state of tissue-wide pathogen alert

Science ◽

10.1126/science.1254803 ◽

2014 ◽

Vol 346 (6205) ◽

pp. 101-105 ◽

Cited By ~ 257

Author(s):

Silvia Ariotti ◽

Marc A. Hogenbirk ◽

Feline E. Dijkgraaf ◽

Lindy L. Visser ◽

Mirjam E. Hoekstra ◽

...

Keyword(s):

T Cells ◽

Cd8 T Cells ◽

Memory T Cells ◽

Mouse Skin ◽

Memory Cd8 T Cells ◽

Vaccination Strategies ◽

Rapid Control ◽

Pathogen Entry ◽

Specific Tissue ◽

Resident Memory T Cells

After an infection, pathogen-specific tissue-resident memory T cells (TRM cells) persist in nonlymphoid tissues to provide rapid control upon reinfection, and vaccination strategies that create TRM cell pools at sites of pathogen entry are therefore attractive. However, it is not well understood how TRM cells provide such pathogen protection. Here, we demonstrate that activated TRM cells in mouse skin profoundly alter the local tissue environment by inducing a number of broadly active antiviral and antibacterial genes. This “pathogen alert” allows skin TRM cells to protect against an antigenically unrelated virus. These data describe a mechanism by which tissue-resident memory CD8+ T cells protect previously infected sites that is rapid, amplifies the activation of a small number of cells into an organ-wide response, and has the capacity to control escape variants.

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Memory CD8+ T cells elicited by HIV-1 lipopeptide vaccines display similar phenotypic profiles but differences in term of magnitude and multifunctionality compared with FLU- or EBV-specific memory T cells in humans

Vaccine ◽

10.1016/j.vaccine.2013.11.052 ◽

2014 ◽

Vol 32 (4) ◽

pp. 492-501 ◽

Cited By ~ 4

Author(s):

Suzanne Figueiredo ◽

Benedicte Charmeteau ◽

Mathieu Surenaud ◽

Dominique Salmon ◽

Odile Launay ◽

...

Keyword(s):

T Cells ◽

Cd8 T Cells ◽

Memory T Cells ◽

Memory Cd8 T Cells ◽

Specific Memory ◽

Hiv 1

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Tissue-resident memory T cell reactivation by diverse antigen-presenting cells imparts distinct functional responses

Journal of Experimental Medicine ◽

10.1084/jem.20192291 ◽

2020 ◽

Vol 217 (8) ◽

Cited By ~ 6

Author(s):

Jun Siong Low ◽

Yagmur Farsakoglu ◽

Maria Carolina Amezcua Vesely ◽

Esen Sefik ◽

Joseph B. Kelly ◽

...

Keyword(s):

T Cells ◽

Memory T Cells ◽

Functional Responses ◽

Memory Cd8 T Cells ◽

Cell Reactivation ◽

Gfp Reporter ◽

Antigen Presenting ◽

Resident Memory T Cells

CD8+ tissue-resident memory T cells (TRM cells) are poised at the portals of infection and provide long-term protective immunity. Despite their critical roles, the precise mechanics governing TRM cell reactivation in situ are unknown. Using a TCR-transgenic Nur77-GFP reporter to distinguish “antigen-specific” from “bystander” reactivation, we demonstrate that lung CD8+ TRM cells are reactivated more quickly, yet less efficiently, than their counterparts in the draining LNs (TLN cells). Global profiling of reactivated memory T cells revealed tissue-defined and temporally regulated recall response programs. Unlike the reactivation of CD8+ TLN cells, which is strictly dependent on CD11c+XCR1+ APCs, numerous antigen-presenting partners, both hematopoietic and non-hematopoietic, were sufficient to reactivate lung CD8+ TRM cells, but the quality of TRM cell functional responses depended on the identity of the APCs. Together, this work uncovers fundamental differences in the activation kinetics, mechanics, and effector responses between CD8+ memory T cells in peripheral vs. lymphoid organs, revealing a novel tissue-specific paradigm for the reactivation of memory CD8+ T cells.

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The Emerging Interplay Between Recirculating and Tissue-Resident Memory T Cells in Cancer Immunity: Lessons Learned From PD-1/PD-L1 Blockade Therapy and Remaining Gaps

Frontiers in Immunology ◽

10.3389/fimmu.2021.755304 ◽

2021 ◽

Vol 12 ◽

Author(s):

Silvia Gitto ◽

Ambra Natalini ◽

Fabrizio Antonangeli ◽

Francesca Di Rosa

Keyword(s):

T Cells ◽

T Cell ◽

Solid Tumors ◽

Memory T Cells ◽

Tumor Therapy ◽

T Cell Response ◽

Lessons Learned ◽

Tumor Control ◽

Specific Memory ◽

Resident Memory T Cells

Remarkable progress has been made in the field of anti-tumor immunity, nevertheless many questions are still open. Thus, even though memory T cells have been implicated in long-term anti-tumor protection, particularly in prevention of cancer recurrence, the bases of their variable effectiveness in tumor patients are poorly understood. Two types of memory T cells have been described according to their traffic pathways: recirculating and tissue-resident memory T cells. Recirculating tumor-specific memory T cells are found in the cell infiltrate of solid tumors, in the lymph and in the peripheral blood, and they constantly migrate in and out of lymph nodes, spleen, and bone marrow. Tissue-resident tumor-specific memory T cells (TRM) permanently reside in the tumor, providing local protection.Anti-PD-1/PD-L1, a type of immune checkpoint blockade (ICB) therapy, can considerably re-invigorate T cell response and lead to successful tumor control, even in patients at advanced stages. Indeed, ICB has led to unprecedented successes against many types of cancers, starting a ground-breaking revolution in tumor therapy. Unfortunately, not all patients are responsive to such treatment, thus further improvements are urgently needed. The mechanisms underlying resistance to ICB are still largely unknown. A better knowledge of the dynamics of the immune response driven by the two types of memory T cells before and after anti-PD-1/PD-L1 would provide important insights on the variability of the outcomes. This would be instrumental to design new treatments to overcome resistance.Here we provide an overview of T cell contribution to immunity against solid tumors, focusing on memory T cells. We summarize recent evidence on the involvement of recirculating memory T cells and TRM in anti-PD-1/PD-L1-elicited antitumor immunity, outline the open questions in the field, and propose that a synergic action of the two types of memory T cells is required to achieve a full response. We argue that a T-centric vision focused on the specific roles and the possible interplay between TRM and recirculating memory T cells will lead to a better understanding of anti-PD-1/PD-L1 mechanism of action, and provide new tools for improving ICB therapeutic strategy.

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