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Identification of Novel Innate Immune Checkpoint Receptors

Award Number: R21CA306039
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/13/2026
PERIOD OF PERFORMANCE END DATE: 04/30/2027

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Identification of Novel Innate Immune Checkpoint Receptors - PROJECT SUMMARY Immunotherapies targeting adaptive immune checkpoints have improved cancer outcomes, but innate immune checkpoints also play crucial roles in cancer immune evasion and are promising targets for immunotherapy. The innate immune system uses eat-me and don’t-eat-me signals to regulate phagocytosis, essential for maintaining tissue homeostasis and preventing cancer. Phagocytic cells have also recently emerged as new key actors in the success of immunologically mismatched allograft transplants through human leucocyte antigens (HLA) allorecognition. Thus, identifying the molecular patterns and receptors governing phagocytosis is vital for understanding cancer clearance and transplantation. Recently published studies of the PI revealed novel functions for Vascular Cell Adhesion Molecule-1 (VCAM1) on healthy and malignant hematopoietic stem cells (HSCs). We have found that VCAM1 is highly expressed on healthy HSCs, serving as an innate immune checkpoint for entry into the bone marrow by providing a don't-eat-me signal in the context of major histocompatibility complex (MHC) class-I presentation. In addition, we found that leukemia cells exploit this tolerance mechanism to avoid innate immune recognition, suggesting that the VCAM1-receptor axis is a promising target for immunotherapy. However, the specific receptor mediating this interaction remains unknown. In preliminary studies, we employed proteomics and AlphaFold modeling to identify novel VCAM1 receptor candidates on phagocytic cells. Our Specific Aim 1 focuses on identifying the VCAM1 receptor promoting immune tolerance and leukemia evasion and validating its function in vitro and in vivo using mouse and human models of leukemia. Specific Aim 2 will assess the impact of inhibiting or deleting VCAM1 receptor signaling on myeloid and lymphoid leukemia cell clearance, as well as allogeneic transplantation outcomes. Successful completion of this research will advance knowledge of innate immune recognition mechanisms, identify new leukemia immunotherapy targets, and improve outcomes in stem cell transplantation. 1


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 = $412,249 )
2026	2026	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD AVE M/C 551	CHICAGO	IL	60612	COOK	USA	Cancer Biology Research	000	1	5/14/2026	NEW	$412,249
														Subtotal = $412,249

Grand Total All Awards = $412,249

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Identification of Novel Innate Immune Checkpoint Receptors

Award Number: R21CA306039

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/13/2026

PERIOD OF PERFORMANCE END DATE: 04/30/2027

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