CXCR6 positions cytotoxic T cells to receive critical survival signals in the tumor microenvironment

Pilato, Mauro Di; Kfuri-Rubens, Raphael; Pruessmann, Jasper N.; Ozga, Aleksandra J.; Messemaker, Marius; Cadilha, Bruno L.; Sivakumar, Ramya; Cianciaruso, Chiara; Warner, Ross D.; Marangoni, Francesco; Carrizosa, Esteban; Lesch, Stefanie; Billingsley, James M.; Pérez-Ramos, Daniel W.; Zavala, Fidel; Rheinbay, Esther; Luster, Andrew D.; Gerner, Michael Y.; Kobold, Sebastian; Pittet, Mikaël J.; Mempel, Thorsten R.

doi:10.1016/j.cell.2021.07.015

Cited by 233 publications

(220 citation statements)

References 87 publications

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“…Whether the reduced delivery of antigens to the draining lymph nodes limits the durability of the response to TIM-3 blockade, and how this might impact the efficacy of αPD-1, remains to be determined. Regardless, combined with the recent description of CXCL16 production by cDCs leading to enhanced CD8 + T cell survival through IL-15 transpresentation, 34 these findings underscore an important role for tumor cDCs in regulating the spatial distribution of CD8 + T cells and promoting their effector function via cytokines.…”

Section: Discussionmentioning

confidence: 82%

TIM-3 blockade enhances IL-12-dependent antitumor immunity by promoting CD8⁺T cell and XCR1⁺dendritic cell spatial co-localization

Gardner

Pulido

Hänggi

et al. 2022

J Immunother Cancer

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BackgroundT cell immunoglobulin and mucin domain containing−3 (TIM-3) blocking antibodies are currently being evaluated in clinical trials for solid and hematological malignancies. Despite its identification on T cells, TIM-3 is predominantly expressed by myeloid cells, including XCR1+ type I conventional dendritic cells (cDC1s). We have recently shown that TIM-3 blockade promotes expression of CXCR3 chemokine ligands by tumor cDCs, but how this drives a CD8+ T cell-dependent response to therapy is unclear.MethodsT cell infiltration, effector function, and spatial localization in relation to XCR1+ cDC1s were evaluated in a murine orthotopic mammary carcinoma model during response to TIM-3 blockade and paclitaxel chemotherapy. Mixed bone marrow chimeras and diphtheria toxin depletion were used to determine the role of specific genes in cDC1s during therapeutic responses.ResultsTIM-3 blockade increased interferon-γ expression by CD8+ T cells without altering immune infiltration. cDC1 expression of CXCL9, but not CXCL10, was required for response to TIM-3 blockade. CXCL9 was also necessary for the increased proximity observed between CD8+ T cells and XCR1+ cDC1s during therapy. Tumor responses were dependent on cDC1 expression of interleukin-12, but not MHCI.ConclusionsTIM-3 blockade increases exposure of intratumoral CD8+ T cells to cDC1-derived cytokines, with implications for the design of therapeutic strategies using antibodies against TIM-3.

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Section: Discussionmentioning

confidence: 82%

TIM-3 blockade enhances IL-12-dependent antitumor immunity by promoting CD8⁺T cell and XCR1⁺dendritic cell spatial co-localization

Gardner

Pulido

Hänggi

et al. 2022

J Immunother Cancer

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“…Conversely, HC cells expressing Th2 cytokines are selectively excluded from tumor extravasation in the current setting. Another possibility is that the vascular niche favors the survival of anti-tumoral cytotoxic T cells [ 38 ]. Thus, Shb -deficient EC would not be expected to support a microenvironment that promotes an active anti-tumoral immune response.…”

Section: Discussionmentioning

confidence: 99%

Mouse Breast Carcinoma Monocytic/Macrophagic Myeloid-Derived Suppressor Cell Infiltration as a Consequence of Endothelial Dysfunction in Shb-Deficient Endothelial Cells Increases Tumor Lung Metastasis

Jamalpour

Bergquist

et al. 2021

IJMS

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Metastasis reflects both the inherent properties of tumor cells and the response of the stroma to the presence of the tumor. Vascular barrier properties, either due to endothelial cell (EC) or pericyte function, play an important role in metastasis in addition to the contribution of the immune system. The Shb gene encodes the Src homology-2 domain protein B that operates downstream of tyrosine kinases in both vascular and immune cells. We have investigated E0771.lmb breast carcinoma metastasis in mice with conditional deletion of the Shb gene using the Cdh5-CreERt2 transgene, resulting in inactivation of the Shb-gene in EC and some hematopoietic cell populations. Lung metastasis from orthotopic tumors, tumor vascular and immune cell characteristics, and immune cell gene expression profiles were determined. We found no increase in vascular leakage that could explain the observed increase in metastasis upon the loss of Shb expression. Instead, Shb deficiency in EC promoted the recruitment of monocytic/macrophagic myeloid-derived suppressor cells (mMDSC), an immune cell type that confers a suppressive immune response, thus enhancing lung metastasis. An MDSC-promoting cytokine/chemokine profile was simultaneously observed in tumors grown in mice with EC-specific Shb deficiency, providing an explanation for the expanded mMDSC population. The results demonstrate an intricate interplay between tumor EC and immune cells that pivots between pro-tumoral and anti-tumoral properties, depending on relevant genetic and/or environmental factors operating in the microenvironment.

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“…This ability to utilize longer wavelength light allows for deeper penetration of photons into tissues, and the requirement for spatial convergence of two photons at a very precise focal plane yields less out-of-focus fluorescence excitation, photobleaching, and phototoxicity. This technology has allowed researchers to visualize immune cell function within intact organs that were outside the depth of standard confocal, such as the spleen, lymph nodes, brain, tumors, and deep within other solid organs [ 26 , 27 , 28 , 29 ]. Furthermore, multiphoton imaging provides added benefits such as label-free second harmonic detection of organized tissue structures, such as collagen architecture [ 30 ].…”

Section: Seeing Is Believing—in Vivo Imaging Of Neutrophil Trafficking and Functionmentioning

confidence: 99%

A Multi-Modal Toolkit for Studying Neutrophils in Cancer and Beyond

Changirwa

Schlechte

McDonald

2021

Cancers

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As key effector cells of the innate immune response, neutrophils are rapidly deployed to sites of inflammation where they deliver a payload of potent effector mechanisms that are essential for host defense against pathogens as well as tissue homeostasis. In addition, neutrophils are central contributors to the pathogenesis of a vast spectrum of inflammatory, degenerative, and neoplastic diseases. As our understanding of neutrophils in health and disease continually expands, so too does our appreciation of their complex and dynamic nature in vivo; from development, maturation, and trafficking to cellular heterogeneity and functional plasticity. Therefore, contemporary neutrophil research relies on multiple complementary methodologies to perform integrated analysis of neutrophil phenotypic heterogeneity, organ- and stimulus-specific trafficking mechanisms, as well as tailored effector functions in vivo. This review discusses established and emerging technologies used to study neutrophils, with a focus on in vivo imaging in animal models, as well as next-generation ex vivo model systems to study mechanisms of neutrophil function. Furthermore, we discuss how high-dimensional single-cell analysis technologies are driving a renaissance in neutrophil biology by redefining our understanding of neutrophil development, heterogeneity, and functional plasticity. Finally, we discuss innovative applications and emerging opportunities to integrate these high-dimensional, multi-modal techniques to deepen our understanding of neutrophils in cancer research and beyond.

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CXCR6 positions cytotoxic T cells to receive critical survival signals in the tumor microenvironment

Cited by 233 publications

References 87 publications

TIM-3 blockade enhances IL-12-dependent antitumor immunity by promoting CD8⁺T cell and XCR1⁺dendritic cell spatial co-localization

TIM-3 blockade enhances IL-12-dependent antitumor immunity by promoting CD8⁺T cell and XCR1⁺dendritic cell spatial co-localization

Mouse Breast Carcinoma Monocytic/Macrophagic Myeloid-Derived Suppressor Cell Infiltration as a Consequence of Endothelial Dysfunction in Shb-Deficient Endothelial Cells Increases Tumor Lung Metastasis

A Multi-Modal Toolkit for Studying Neutrophils in Cancer and Beyond

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CXCR6 positions cytotoxic T cells to receive critical survival signals in the tumor microenvironment

Cited by 233 publications

References 87 publications

TIM-3 blockade enhances IL-12-dependent antitumor immunity by promoting CD8+T cell and XCR1+dendritic cell spatial co-localization

TIM-3 blockade enhances IL-12-dependent antitumor immunity by promoting CD8+T cell and XCR1+dendritic cell spatial co-localization

Mouse Breast Carcinoma Monocytic/Macrophagic Myeloid-Derived Suppressor Cell Infiltration as a Consequence of Endothelial Dysfunction in Shb-Deficient Endothelial Cells Increases Tumor Lung Metastasis

A Multi-Modal Toolkit for Studying Neutrophils in Cancer and Beyond

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Product

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TIM-3 blockade enhances IL-12-dependent antitumor immunity by promoting CD8⁺T cell and XCR1⁺dendritic cell spatial co-localization

TIM-3 blockade enhances IL-12-dependent antitumor immunity by promoting CD8⁺T cell and XCR1⁺dendritic cell spatial co-localization