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Investigating CD200 Signaling as a Regulator of Immunosuppression and Osteoclastogenesis in Bone Metastatic Niche

Award Number: K00CA294171
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2024
PERIOD OF PERFORMANCE END DATE: 06/30/2030

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Investigating CD200 Signaling as a Regulator of Immunosuppression and Osteoclastogenesis in Bone Metastatic Niche - PROJECT SUMMARY Immune checkpoint inhibitors (ICIs) enable anti-tumor immunity by blocking immunoregulatory receptor-ligand interactions (e.g., programmed cell death protein 1 [PD-1] and its ligand [PD-L1]). Despite their widespread success as an anti-cancer therapy, ICIs function poorly in patients with bone metastases, and patients receiving therapy are at risk of developing bone loss and fractures. I have previously observed bone loss, immune suppression, and no reduction in bone metastatic tumor burden in mice inoculated with murine breast cancer cells and treated with a PD-1 inhibitor. Given that many breast cancer survivors will succumb to the disease due to residual tumor cells that evade therapy, understanding the mechanisms of immune suppression in the bone metastatic niche is critical. CD200 has been indicated as an immunoregulatory gene enriched in dormant tumor populations commonly associated with the bone marrow niche and its receptor, CD200R, is primarily expressed on myeloid lineage cells including osteoclast precursors. Thus, increased signaling through the CD200/CD200R axis may promote T cell dysfunction directly, promote osteoclastogenesis, and amplify the “vicious cycle” of bone metastasis in which tumor-induced bone resorption fuels tumor growth and immunosuppression. I hypothesize that CD200 signaling reprograms BM myeloid lineage cells to suppress T cell activity and promote osteoclastogenesis, thereby contributing to bone metastatic resistance to ICI therapy. The use of immunocompetent mouse models is essential for the proposed studies; the bone metastatic microenvironment is composed of dynamic interactions between tumor cells, immune cells, and bone tissue that cannot be adequately modeled in vitro. To test this hypothesis, I propose to (1) define how CD200/CD200R shapes immune composition and T cell function in the bone metastatic microenvironment, (2) determine whether CD200 signaling in bone metastases promotes osteoclastogenesis, and (3) determine whether targeting CD200 enhances response to ICI therapy in a bone metastatic setting. In Aim 1, I will combine in vitro profiling combined with in vivo functional studies to define how CD200 signaling shapes myeloid-mediated immunomodulatory mechanisms and T cell function in the bone metastatic niche. In Aim 2, I will treat xenoantigen-tolerant “NoGlow” mice with CD200lo or CD200hi breast cancer cells and/or a CD200 inhibitor to dissect the relative contributions of tumor- vs host-derived CD200 signaling in driving pathogenic osteoclastogenesis during bone metastasis. In Aim 3, I will use in vivo approaches to evaluate therapeutic targets to increase long-term ICI efficacy in patients with bone metastases. Given the high incidence of bone metastases for multiple tumor types and the poor survival of bone metastatic patients in response to ICI therapy, this proposal will help identify molecular mechanisms driving immune resistance in the bone niche and reveal new therapeutic opportunities for improving outcomes in patients with bone metastatic disease.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $98,702 )
2026	2026	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Cancer Cause and Prevention Research	000	3	9/3/2026	EXTENSION WITH OR WITHOUT FUNDS	$98,702
														Subtotal = $98,702

Grand Total All Awards = $98,702

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Investigating CD200 Signaling as a Regulator of Immunosuppression and Osteoclastogenesis in Bone Metastatic Niche

Award Number: K00CA294171

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/01/2024

PERIOD OF PERFORMANCE END DATE: 06/30/2030

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