Broad immunophenotyping of the murine brain tumor microenvironment

Tomaszewski, William H.; Polania, Jessica Waibl; Miggelbrink, Alexandra; Chakraborty, Molly Antara; Fecci, Peter E.; Sampson, John H.; Gunn, Michael D.

doi:10.1016/j.jim.2021.113158

Cited by 5 publications

(4 citation statements)

References 14 publications

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“…Procedures for tissue processing and flow cytometry are based on our previously published protocols 54 . Briefly, mice were anesthetized with isoflurane before undergoing cardiac puncture and perfusion with PBS.…”

Section: Methodsmentioning

confidence: 99%

IL-7 mediated upregulation of VLA-4 increases accumulation of adoptively transferred T lymphocytes in murine glioma.

Singh,

Hotchkiss,

Cook

et al. 2024

Preprint

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The efficacy of T cell-dependent immunotherapies against glioma is limited by few intra-tumoral lymphocytes and tumor-induced T cell sequestration. We considered whether peripheral autologous lymphocyte transfer (ALT) could boost Central Nervous System (CNS) T cell counts in established glioma. We found that ALT lymphocytes specifically entered tumor tissue while endogenous T cell counts fell. T cells expanded with IL-7 demonstrated an enhanced ability to accumulate in established murine glioma compared to IL-2. Increased entry was not phenotype dependent. Instead, IL-7 upregulates the migratory integrin VLA-4 on mouse and human T cells. VLA-4 expression was also high on endogenous T cells in established tumors. Intracranial (IC) VLA-4 blockade retained T cells in the brain but did not yield any survival benefit. IC VLA-4 blockade also reduced the cytotoxicity of immunotherapies in vitro. However, combination IL-7 ALT (VLA-4Hi) & α4-1BB antibody therapy extended median survival for animals with orthotopic glioma compared to monotherapy. Similarly, IL-7 expanded hPBMCs & brain bi-specific T cell engagers targeting EGFRvIII (BRiTE) extended survival. We conclude that IL-7 upregulates VLA-4 on T cells, facilitating their accumulation in IC glioma. Seeding gliomas with infiltrative T cells is a potential therapeutic strategy to enhance the efficacy of T-cell dependent therapies.

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Section: Methodsmentioning

confidence: 99%

IL-7 mediated upregulation of VLA-4 increases accumulation of adoptively transferred T lymphocytes in murine glioma.

Singh,

Hotchkiss,

Cook

et al. 2024

Preprint

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“…A detailed protocol for processing and staining tumors can be found in ref. 56 . In brief, after perfusion with PBS and 1% heparin, tumor-bearing hemispheres were collected on day 18 after tumor implantation.…”

Section: Methodsmentioning

confidence: 99%

CD8+ T cells maintain killing of MHC-I-negative tumor cells through the NKG2D–NKG2DL axis

et al. 2023

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The accepted paradigm for both cellular and anti-tumor immunity relies upon tumor cell killing by CD8+ T cells recognizing cognate antigens presented in the context of target cell major histocompatibility complex (MHC) class I (MHC-I) molecules. Likewise, a classically described mechanism of tumor immune escape is tumor MHC-I downregulation. Here, we report that CD8+ T cells maintain the capacity to kill tumor cells that are entirely devoid of MHC-I expression. This capacity proves to be dependent instead on interactions between T cell natural killer group 2D (NKG2D) and tumor NKG2D ligands (NKG2DLs), the latter of which are highly expressed on MHC-loss variants. Necessarily, tumor cell killing in these instances is antigen independent, although prior T cell antigen-specific activation is required and can be furnished by myeloid cells or even neighboring MHC-replete tumor cells. In this manner, adaptive priming can beget innate killing. These mechanisms are active in vivo in mice as well as in vitro in human tumor systems and are obviated by NKG2D knockout or blockade. These studies challenge the long-advanced notion that downregulation of MHC-I is a viable means of tumor immune escape and instead identify the NKG2D–NKG2DL axis as a therapeutic target for enhancing T cell-dependent anti-tumor immunity against MHC-loss variants.

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“…A detailed protocol for processing and staining tumors can be found here[51]. In brief, after perfusion with PBS + heparin 1%, tumor-bearing hemispheres were harvested.…”

Section: Methodsmentioning

confidence: 99%

A Novel MHC-Independent Mechanism of Tumor Cell Killing by CD8⁺T Cells

Lerner

Woroniecka

D’Anniballe

et al. 2023

Preprint

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The accepted paradigm for both cellular and antitumor immunity relies upon tumor cell kill by CD8+ T cells recognizing cognate antigens presented in the context of target cell major histocompatibility complex class I (MHC I) molecules. Likewise, a classically described mechanism of tumor immune escape is tumor MHC-I downregulation. Here, we report that CD8+ T cells maintain the capacity to kill tumor cells that are entirely devoid of MHC-I expression. This capacity proves to be dependent on interactions between T cell NKG2D and tumor NKG2D ligands (NKG2DL). Necessarily, tumor cell kill in these instances is antigen-independent, although prior T cell antigen specific activation is required and can be furnished by myeloid cells or even neighboring MHC-replete tumors cells. These mechanisms are active in vivo in mice, as well as in vitro in human tumor systems, and are obviated by NKG2D knockout or blockade. Tumor cell killing following T cell NKG2D engagement is Fas-independent and appears to involve granzyme. These studies potentially obviate the long-advanced notion that downregulation of MHC-I is a viable means of tumor immune escape, and instead identify the NKG2D/NKG2DL axis as a novel therapeutic target for enhancing T cell-dependent anti tumor immunity against MHC loss variants.

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Broad immunophenotyping of the murine brain tumor microenvironment

Cited by 5 publications

References 14 publications

IL-7 mediated upregulation of VLA-4 increases accumulation of adoptively transferred T lymphocytes in murine glioma.

IL-7 mediated upregulation of VLA-4 increases accumulation of adoptively transferred T lymphocytes in murine glioma.

CD8+ T cells maintain killing of MHC-I-negative tumor cells through the NKG2D–NKG2DL axis

A Novel MHC-Independent Mechanism of Tumor Cell Killing by CD8⁺T Cells

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Broad immunophenotyping of the murine brain tumor microenvironment

Cited by 5 publications

References 14 publications

IL-7 mediated upregulation of VLA-4 increases accumulation of adoptively transferred T lymphocytes in murine glioma.

IL-7 mediated upregulation of VLA-4 increases accumulation of adoptively transferred T lymphocytes in murine glioma.

CD8+ T cells maintain killing of MHC-I-negative tumor cells through the NKG2D–NKG2DL axis

A Novel MHC-Independent Mechanism of Tumor Cell Killing by CD8+T Cells

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A Novel MHC-Independent Mechanism of Tumor Cell Killing by CD8⁺T Cells