ACKR4 restrains antitumor immunity by regulating CCL21

Area of Science:

• Immunology
• Oncology
• Cell Biology

Background:

• Current immunotherapies show promise but face limitations in solid tumors due to low tumor-specific T cell presence.
• The tumor microenvironment (TME) plays a critical role in regulating anti-tumor immune responses.
• Understanding factors controlling T cell infiltration and activation in the TME is crucial for enhancing cancer treatments.

Purpose of the Study:

• To investigate the role of atypical chemokine receptor 4 (ACKR4) in regulating intratumor T cell responses.
• To determine the impact of ACKR4 on CD8+ T cell accumulation and activation within the tumor microenvironment.
• To explore ACKR4 and CCL21 as potential therapeutic targets for improving cancer immunotherapy.

Main Methods:

• Utilized mouse models to study the effects of ACKR4 deficiency on tumor growth and T cell infiltration.
• Analyzed the expression and function of ACKR4 in nonhematopoietic cells within the TME.
• Investigated the regulatory mechanisms of ACKR4 on dendritic cell retention and chemokine levels (CCL21) in tumors.

Main Results:

• Absence of ACKR4 led to increased intratumor CD8+ T cells, which inhibited tumor growth.
• Nonhematopoietic ACKR4 expression was essential for controlling T cell accumulation.
• ACKR4 was found to inhibit CD103+ dendritic cell retention by regulating intratumor CCL21 levels.

Conclusions:

• Host ACKR4 acts as a critical regulator limiting CD8+ T cell accumulation and activation in the tumor microenvironment.
• ACKR4-mediated regulation of CCL21 influences dendritic cell retention and T cell infiltration.
• Targeting ACKR4 and CCL21 presents a promising strategy to enhance the efficacy of immunotherapies like immune checkpoint blockade.