IMPACT OF CIRCULATING MYELOID CELL CLUSTERS ON ANTI-TUMOR IMMUNITY - DURABLE OUTCOMES IN SUBSETS OF SOLID C…

Assistance award details

Assistance award identifier

ASST_NON_R01CA250412_075

FAIN

R01CA250412

Recipient

HEALTH RESEARCH, INC.

Awarding agency

Department of Health and Human Services

Funding agency

Department of Health and Human Services

Assistance listing (CFDA)

93.396

Total obligated

$3,445,316

Period

Jan 1, 2021 – Dec 31, 2025

Fiscal year

2021

Place of performance state

NY

Source file

FY2021_All_Assistance_Full_20261006.zip

Description

IMPACT OF CIRCULATING MYELOID CELL CLUSTERS ON ANTI-TUMOR IMMUNITY - DURABLE OUTCOMES IN SUBSETS OF SOLID CANCER PATIENTS TREATED WITH IMMUNE CHECKPOINT INHIBITORS (ICI) OR ADOPTIVE CELL TRANSFER (ACT) IMMUNOTHERAPY HAS DRIVEN INTEREST IN GAINING A BETTER UNDERSTANDING OF RESISTANCE MECHANISMS THAT COULD IDENTIFY NOVEL DRUGGABLE TARGETS. MYELOID-DERIVED SUPPRESSOR CELLS (MDSC) HAVE EMERGED AS ONE SUCH BARRIER BASED ON THEIR ABILITY TO INHIBIT INNATE AND ADAPTIVE IMMUNITY. WHILE ELEVATED BLOOD MDSC ARE RECOGNIZED AS A POOR PROGNOSTIC INDICATOR IN CANCER PATIENTS, IT IS WIDELY THOUGHT THAT THE MAIN EFFECTOR SITE FOR MDSC IS WITHIN THE TUMOR MICROENVIRONMENT (TME). THIS IS IN LINE WITH THE WELL-DOCUMENTED CONTACT- DEPENDENT MECHANISMS INVOLVING SHORT-LIVED INTERMEDIATES THAT UNDERLIE KNOWN MECHANISMS OF T CELL SUPPRESSION BY MDSC. OUR PUBLISHED AND PRELIMINARY STUDIES ENLARGE ON THIS VIEW, SHOWING THAT MDSC ALSO FUNCTION OUTSIDE THE TME THROUGH AN UNPRECEDENTED MECHANISM OF INTRAVASCULAR IMMUNE SUPPRESSION. THE PROPOSED STUDY BUILDS ON OUR DISCOVERY THAT CIRCULATING MDSC INITIATE CONTACT-DEPENDENT CLEAVAGE OF THE L- SELECTIN HOMING RECEPTOR ON TARGET T CELLS THAT SUBSTANTIALLY REDUCES ANTIGEN-DRIVEN EXPANSION OF CYTOTOXIC T CELLS IN LYMPH NODES. WE FURTHER FOUND THAT L-SELECTIN LOSS COINCIDES WITH THE FORMATION OF STABLE MDSC CLUSTERS IN THE BLOOD OF MURINE TUMOR MODELS AND ADVANCED CANCER PATIENTS. WE TERM THESE NEW STRUCTURES CIRCULATING MYELOID CELL (CMC) CLUSTERS. THESE OBSERVATIONS LED US TO HYPOTHESIZE THAT CMC CLUSTERS ARE AN UNRECOGNIZED FUNCTIONAL NICHE FOR SYSTEMIC IMMUNE SUPPRESSION IN CANCER. TO TEST THIS HYPOTHESIS, WE WILL FIRST DETERMINE IF BLOOD-BORNE MDSC TARGET NOT ONLY NAÏVE T CELLS, BUT MORE BROADLY ATTACK STEM CELL MEMORY AND CENTRAL MEMORY T CELLS AND NATURAL KILLER CELLS THAT EACH REQUIRE L-SELECTIN FOR THEIR ANTITUMOR ACTIVITY. SECONDLY, WE WILL DETERMINE IF CMC CLUSTERS ARE THE ACTIVE SITE OF L-SELECTIN CLEAVAGE BY USING A MULTIPRONGED GENETIC