Coupling dead cell recognition to Fcγ receptors augments anticancer immunity

Area of Science:

• Immunology
• Cancer Biology
• Cellular Biology

Background:

• Type 1 conventional dendritic cells (cDC1s) are crucial for initiating anti-cancer CD8+ T cell responses via cross-presentation of tumor antigens.
• cDC1s utilize the DNGR-1 receptor to bind F-actin on dead cells, facilitating antigen capture and cross-presentation.
• The scarcity of cDC1s within tumors limits their effectiveness in driving anti-cancer immunity.

Purpose of the Study:

• To investigate methods for redirecting abundant, non-specialized antigen-presenting cells (APCs) to perform cross-presentation of tumor antigens.
• To evaluate the efficacy of F-actin-FcγR bridging strategies in enhancing anti-cancer immunity.
• To explore the potential of F-actin-FcγR bridging in combination with existing cancer therapies.

Main Methods:

• Development and application of reagents, including an Fc-DNGR-1 fusion protein and an anti-F-actin antibody, to bridge F-actin on necrotic debris to Fcγ receptors (FcγRs) on APCs.
• In vivo studies using mouse cancer models to assess the accumulation of Fc-DNGR-1 in tumors and its interaction with FcγR+ APCs.
• Evaluation of tumor control and synergy with chemotherapy or radiotherapy following F-actin-FcγR bridging interventions.

Main Results:

• Abundant tumor-associated APCs, including cDC2s and monocyte-derived cells, can be redirected to internalize necrotic debris and cross-present antigens through F-actin-FcγR bridging.
• Fc-DNGR-1 fusion protein effectively accumulates in necrotic tumor regions, localizing near intratumoral FcγR+ APCs.
• F-actin-FcγR bridging significantly enhanced tumor control in mouse cancer models and demonstrated synergistic effects with cytotoxic chemotherapy and radiotherapy.

Conclusions:

• Nonspecialized APCs can be effectively harnessed for the cross-presentation of necrotic tumor antigens.
• F-actin-FcγR bridging represents a promising strategy to potentiate anti-cancer immunity by engaging a broader range of APCs.
• This approach offers a novel therapeutic avenue for enhancing anti-cancer immune responses, particularly in combination with conventional treatments.