ACKR4 in Tumor Cells Regulates Dendritic Cell Migration to Tumor-Draining Lymph Nodes and T-Cell Priming

Dechen Wangmo; Prem K. Premsrirut; Ce Yuan; William S. Morris; Xianda Zhao; Subree Subramanian

doi:10.3390/cancers13195021

ACKR4 in Tumor Cells Regulates Dendritic Cell Migration to Tumor-Draining Lymph Nodes and T-Cell Priming

Dechen Wangmo, Prem K. Premsrirut, Ce Yuan, William S. Morris, Xianda Zhao, Subree Subramanian

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Abstract

Colorectal cancer (CRC) is one of the most common malignancies in both morbidity and mortality. Immune checkpoint blockade (ICB) treatments have been successful in a portion of mismatch repair-deficient (dMMR) CRC patients but have failed in mismatch repair-proficient (pMMR) CRC patients. Atypical Chemokine Receptor 4 (ACKR4) is implicated in regulating dendritic cell (DC) migration. However, the roles of ACKR4 in CRC development and anti-tumor immunoregu-lation are not known. By analyzing human CRC tissues, transgenic animals, and genetically modi-fied CRC cells lines, our study revealed an important function of ACKR4 in maintaining CRC immune response. Loss of ACKR4 in CRC is associated with poor immune infiltration in the tumor microenvironment. More importantly, loss of ACKR4 in CRC tumor cells, rather than stromal cells, restrains the DC migration and antigen presentation to the tumor-draining lymph nodes (TdLNs). Moreover, tumors with ACKR4 knockdown become less sensitive to immune checkpoint blockade. Finally, we identified that microRNA miR-552 negatively regulates ACKR4 expression in human CRC. Taken together, our studies identified a novel and crucial mechanism for the maintenance of the DC-mediated T-cell priming in the TdLNs. These new findings demonstrate a novel mechanism leading to immunosuppression and ICB treatment resistance in CRC.

Original language	English (US)
Article number	5021
Pages (from-to)	5021
Journal	Cancers
Volume	13
Issue number	19
DOIs	https://doi.org/10.3390/cancers13195021
State	Published - Oct 1 2021

Bibliographical note

Funding Information:
Funding: This study was supported by the Minnesota Colorectal Cancer Research Foundation, Mezin Koats Colorectal Cancer Funds, Department of Surgery, University of Minnesota research funds, and the National Institutes of Health grant R03CA219129. Dechen Wangmo was supported by the National Institutes of Health’s National Center for Advancing Translational Sciences, grants TL1R002493 and UL1TR002494. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health’s National Center for Advancing Translational Sciences.

Funding Information:
This study was supported by the Minnesota Colorectal Cancer Research Foundation, Mezin Koats Colorectal Cancer Funds, Department of Surgery, University of Minnesota research funds, and the National Institutes of Health grant R03CA219129. Dechen Wangmo was supported by the National Institutes of Health?s National Center for Advancing Translational Sciences, grants TL1R002493 and UL1TR002494. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health?s National Center for Advancing Translational Sciences.

Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.

Keywords

Atypical Chemokine Receptor 4 (ACKR4)
Colorectal cancer
Dendritic cells
Immune checkpoint blockade
Immune checkpoints
T-cell priming

PubMed: MeSH publication types

Journal Article

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.3390/cancers13195021

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title = "ACKR4 in Tumor Cells Regulates Dendritic Cell Migration to Tumor-Draining Lymph Nodes and T-Cell Priming",

abstract = "Colorectal cancer (CRC) is one of the most common malignancies in both morbidity and mortality. Immune checkpoint blockade (ICB) treatments have been successful in a portion of mismatch repair-deficient (dMMR) CRC patients but have failed in mismatch repair-proficient (pMMR) CRC patients. Atypical Chemokine Receptor 4 (ACKR4) is implicated in regulating dendritic cell (DC) migration. However, the roles of ACKR4 in CRC development and anti-tumor immunoregu-lation are not known. By analyzing human CRC tissues, transgenic animals, and genetically modi-fied CRC cells lines, our study revealed an important function of ACKR4 in maintaining CRC immune response. Loss of ACKR4 in CRC is associated with poor immune infiltration in the tumor microenvironment. More importantly, loss of ACKR4 in CRC tumor cells, rather than stromal cells, restrains the DC migration and antigen presentation to the tumor-draining lymph nodes (TdLNs). Moreover, tumors with ACKR4 knockdown become less sensitive to immune checkpoint blockade. Finally, we identified that microRNA miR-552 negatively regulates ACKR4 expression in human CRC. Taken together, our studies identified a novel and crucial mechanism for the maintenance of the DC-mediated T-cell priming in the TdLNs. These new findings demonstrate a novel mechanism leading to immunosuppression and ICB treatment resistance in CRC.",

keywords = "Atypical Chemokine Receptor 4 (ACKR4), Colorectal cancer, Dendritic cells, Immune checkpoint blockade, Immune checkpoints, T-cell priming",

author = "Dechen Wangmo and Premsrirut, \{Prem K.\} and Ce Yuan and Morris, \{William S.\} and Xianda Zhao and Subree Subramanian",

note = "Funding Information: Funding: This study was supported by the Minnesota Colorectal Cancer Research Foundation, Mezin Koats Colorectal Cancer Funds, Department of Surgery, University of Minnesota research funds, and the National Institutes of Health grant R03CA219129. Dechen Wangmo was supported by the National Institutes of Health{\textquoteright}s National Center for Advancing Translational Sciences, grants TL1R002493 and UL1TR002494. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health{\textquoteright}s National Center for Advancing Translational Sciences. Funding Information: This study was supported by the Minnesota Colorectal Cancer Research Foundation, Mezin Koats Colorectal Cancer Funds, Department of Surgery, University of Minnesota research funds, and the National Institutes of Health grant R03CA219129. Dechen Wangmo was supported by the National Institutes of Health?s National Center for Advancing Translational Sciences, grants TL1R002493 and UL1TR002494. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health?s National Center for Advancing Translational Sciences. Publisher Copyright: {\textcopyright} 2021 by the authors. Licensee MDPI, Basel, Switzerland.",

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AU - Morris, William S.

AU - Zhao, Xianda

AU - Subramanian, Subree

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N2 - Colorectal cancer (CRC) is one of the most common malignancies in both morbidity and mortality. Immune checkpoint blockade (ICB) treatments have been successful in a portion of mismatch repair-deficient (dMMR) CRC patients but have failed in mismatch repair-proficient (pMMR) CRC patients. Atypical Chemokine Receptor 4 (ACKR4) is implicated in regulating dendritic cell (DC) migration. However, the roles of ACKR4 in CRC development and anti-tumor immunoregu-lation are not known. By analyzing human CRC tissues, transgenic animals, and genetically modi-fied CRC cells lines, our study revealed an important function of ACKR4 in maintaining CRC immune response. Loss of ACKR4 in CRC is associated with poor immune infiltration in the tumor microenvironment. More importantly, loss of ACKR4 in CRC tumor cells, rather than stromal cells, restrains the DC migration and antigen presentation to the tumor-draining lymph nodes (TdLNs). Moreover, tumors with ACKR4 knockdown become less sensitive to immune checkpoint blockade. Finally, we identified that microRNA miR-552 negatively regulates ACKR4 expression in human CRC. Taken together, our studies identified a novel and crucial mechanism for the maintenance of the DC-mediated T-cell priming in the TdLNs. These new findings demonstrate a novel mechanism leading to immunosuppression and ICB treatment resistance in CRC.

AB - Colorectal cancer (CRC) is one of the most common malignancies in both morbidity and mortality. Immune checkpoint blockade (ICB) treatments have been successful in a portion of mismatch repair-deficient (dMMR) CRC patients but have failed in mismatch repair-proficient (pMMR) CRC patients. Atypical Chemokine Receptor 4 (ACKR4) is implicated in regulating dendritic cell (DC) migration. However, the roles of ACKR4 in CRC development and anti-tumor immunoregu-lation are not known. By analyzing human CRC tissues, transgenic animals, and genetically modi-fied CRC cells lines, our study revealed an important function of ACKR4 in maintaining CRC immune response. Loss of ACKR4 in CRC is associated with poor immune infiltration in the tumor microenvironment. More importantly, loss of ACKR4 in CRC tumor cells, rather than stromal cells, restrains the DC migration and antigen presentation to the tumor-draining lymph nodes (TdLNs). Moreover, tumors with ACKR4 knockdown become less sensitive to immune checkpoint blockade. Finally, we identified that microRNA miR-552 negatively regulates ACKR4 expression in human CRC. Taken together, our studies identified a novel and crucial mechanism for the maintenance of the DC-mediated T-cell priming in the TdLNs. These new findings demonstrate a novel mechanism leading to immunosuppression and ICB treatment resistance in CRC.

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ACKR4 in Tumor Cells Regulates Dendritic Cell Migration to Tumor-Draining Lymph Nodes and T-Cell Priming

Abstract

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Keywords

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UN SDGs

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