R01DE034386

DISSECTING CCL5 CONTRIBUTION TO ANTIGEN SPECIFIC T CELL RESPONSES IN HEAD AND NECK CANCERS - PROJECT SUMMARY CORRELATIVE STUDIES OF IMMUNE CHECKPOINT BLOCKADE (ICB) SHOW THAT RESPONSE IS HIGHLY DEPENDENT ON THE QUANTITATIVE AND QUALITATIVE STATUS OF PRE-EXISTING ANTITUMOR T CELL CLONES. OF PARTICULAR IMPORTANCE IS THE RESERVOIR OF TISSUE RESIDENT MEMORY (TRM) T CELLS THAT POSITIVELY CORRELATE WITH RESPONSE TO ICB THERAPIES. OUR WORK IN HEAD AND NECK SQUAMOUS CELL CARCINOMAS (HNSCCS) LEADS US TO HYPOTHESIZE THAT TRM T CELLS ARE MAJOR PLAYERS IN THE EARLY ANTI-TUMOR IMMUNE RESPONSE TO IMMUNOTHERAPY AND THAT IDENTIFYING SPECIFIC CHEMOKINE AND CYTOKINE NETWORKS SHAPING THE DEVELOPMENT AND FUNCTIONALITY OF ANTITUMOR TRM CELLS WILL LEAD TO IMPROVED THERAPEUTIC STRATEGIES. USING SCRNASEQ AND SCTCRSEQ OF BASELINE AND ON TREATMENT TUMOR SAMPLES FROM A NOVEL NEOADJUVANT ANTI-PD1 HNSCC CLINICAL TRIAL (NCT02296684), WE DEMONSTRATED THAT RESPONDING TUMORS HAD CLONALLY EXPANDED PUTATIVE TUMOR SPECIFIC EXHAUSTED CD8+ TILS WITH A TRM PROGRAM, CHARACTERIZED BY HIGH CYTOTOXIC POTENTIAL AND ZNF683 EXPRESSION. BY CONTRAST, THE NON-RESPONDER BASELINE TUMOR MICROENVIRONMENT (TME) EXHIBITED RELATIVE ABSENCE OF CYTOTOXIC ZNF683+ TILS AND ACCUMULATION OF HIGHLY EXHAUSTED CLONES. TO DEFINE THE DETERMINANTS OF TRM-DEVELOPMENT, WE PURSUED MECHANISTIC STUDIES USING ANTI-PD1 RESPONSIVE OR RESISTANT HNSCC CELL LINE SYNGENEIC MOUSE MODELS. THIS WORK CONFIRMED THAT ANTITUMOR TRM-CELL ACTIVITY WAS POSITIVELY CORRELATED WITH INCREASED FREQUENCY AND FUNCTIONALITY OF TYPE 1 CONVENTIONAL DENDRITIC CELLS (CDC1) AND WITH ENHANCED CCL5 CHEMOKINE EXPRESSION IN BOTH HUMAN HNSCCS AND MOUSE MODELS. TO EXPAND OUR UNDERSTANDING OF TME AND TUMOR DRAINING LYMPH NODE SPECIFIC CCL5 DEPENDENT MECHANISMS UNDERLYING PRODUCTIVE OR INEFFECTIVE T CELL RESPONSES AGAINST HNSCC, WE WILL DISSECT CCL5 DRIVEN REMODELING OF THE TME INCLUDING DEFINING CELLULAR SOURCES AND ITS TARGET(S). WE WILL EXTEND THESE STUDIES TO HUMAN HNSCCS TO DISSECT CCL5 AND CCR5 CONTRIBUTIONS TO DC:T CELL INTERACTIONS IN FRESH TUMOR EXPLANTS. FINALLY, WE WILL USE A THERAPEUTIC APPROACH WITH A NOVEL ONCOLYTIC VIRUS TARGETED TO EPIDERMAL GROWTH FACTOR EXPRESSING TUMOR CELLS THAT ANCHORS CCL5 IN THE TME. TOGETHER, THIS WORK WILL ADDRESS THE KNOWLEDGE GAP REGARDING THE FACTORS UNDERLYING CYTOTOXIC VERSUS DYSFUNCTIONAL ANTITUMOR TUMOR INFILTRATING LYMPHOCYTES IN THE HNSCC TME.

Dana-Farber Cancer Institute

NIDCR EXTRAMURAL RESEARCH PROVIDES RESEARCH FUNDS TO SUPPORT BASIC, TRANSLATIONAL, AND CLINICAL RESEARCH IN DENTAL, ORAL, AND CRANIOFACIAL HEALTH AND DISEASE THROUGH GRANTS, COOPERATIVE AGREEMENTS, AND CONTRACTS THAT SUPPORT SCIENTISTS WORKING IN INSTITUTIONS THROUGHOUT THE UNITED STATES AND INTERNATIONALLY. EXTRAMURAL PROGRAMS PLAN, DEVELOP, AND MANAGE SCIENTIFIC PRIORITIES THROUGH PORTFOLIO ANALYSES AND CONSULTATION WITH STAKEHOLDERS, ENCOURAGING THE MOST PROMISING DISCOVERIES AND EMERGING TECHNOLOGIES FOR RAPID TRANSLATION TO CLINICAL APPLICATIONS. THE INTEGRATIVE BIOLOGY AND INFECTIOUS DISEASES PROGRAMS SUPPORTS BASIC AND TRANSLATIONAL RESEARCH PROGRAMS ON ORAL MICROBIOLOGY, SALIVARY BIOLOGY AND IMMUNOLOGY, ORAL AND SALIVARY GLAND CANCERS, NEUROSCIENCE OF OROFACIAL PAIN AND TEMPOROMANDIBULAR DISORDERS, MINERALIZED TISSUE PHYSIOLOGY, DENTAL BIOMATERIALS, AND TISSUE ENGINEERING AND REGENERATIVE MEDICINE. THE BRANCH AIMS TO ACCELERATE PROGRESS IN BASIC AND TRANSLATIONAL RESEARCH IN THESE AREAS, AND FURTHER STIMULATE THE DISCOVERY PIPELINE BASED ON CLINICAL NEEDS. THE TRANSLATIONAL GENOMICS RESEARCH PROGRAMS SUPPORTS BASIC AND TRANSLATIONAL RESEARCH IN GENETICS, GENOMICS, DEVELOPMENTAL BIOLOGY, AND DATA SCIENCE TOWARD THE GOAL OF IMPROVING DENTAL, ORAL, AND CRANIOFACIAL HEALTH. THE FOCUS IS ON DECIPHERING THE GENETIC, MOLECULAR, AND CELLULAR MECHANISMS UNDERLYING DENTAL, ORAL, AND CRANIOFACIAL DEVELOPMENT AND ANOMALIES. THE BEHAVIORAL AND SOCIAL SCIENCES RESEARCH PROGRAMS SUPPORTS BASIC AND APPLIED RESEARCH TO PROMOTE ORAL HEALTH, TO PREVENT ORAL DISEASES AND RELATED DISABILITIES, AND TO IMPROVE MANAGEMENT OF CRANIOFACIAL CONDITIONS, DISORDERS, AND INJURY. THE PROGRAM PRIORITIZES MECHANISTIC RESEARCH THAT CONTRIBUTES TO A CUMULATIVE SCIENCE OF BEHAVIOR CHANGE, TO MAXIMIZE THE RIGOR, RELEVANCE, AND DISSEMINATION OF EFFICACIOUS BEHAVIOR CHANGE INTERVENTIONS. THE CLINICAL RESEARCH PROGRAMS SUPPORTS PATIENT-ORIENTED, POPULATION, AND COMMUNITY BASED RESEARCH AIMED AT IMPROVING THE DENTAL, ORAL, AND CRANIOFACIAL HEALTH OF THE NATION. THE CENTER FOCUSES ON A VARIETY OF DISEASES AND CONDITIONS THROUGH CLINICAL TRIALS, EPIDEMIOLOGIC STUDIES, PRACTICE-BASED RESEARCH, THE HIV/AIDS AND ORAL HEALTH PROGRAM, AND STUDIES OF ORAL HEALTH DISPARITIES AND INEQUITIES IN ALL AREAS OF NIDCR PROGRAMMATIC INTEREST. THE PROGRAM ENCOURAGES INVESTIGATIONS THAT HAVE THE POTENTIAL TO TRANSLATE FINDINGS INTO EVIDENCE-BASED CLINICAL APPLICATIONS. THE RESEARCH TRAINING AND CAREER DEVELOPMENT EXTRAMURAL PROGRAMS SPAN THE CAREER STAGES OF SCIENTISTS, SUPPORTING RESEARCH TRAINING AND CAREER DEVELOPMENT FOR PHD AND DUAL DEGREE DDS/DMD-PHD STUDENTS, POSTDOCTORAL SCHOLARS, AND EARLY CAREER, MIDCAREER, AND ESTABLISHED INVESTIGATORS. THE PROGRAMS MANAGE SUPPORT FOR FELLOWSHIPS, RESEARCH TRAINING GRANTS, CAREER DEVELOPMENT AND CAREER TRANSITION AWARDS, NIH LOAN REPAYMENT AWARDS, AND DIVERSITY SUPPLEMENTS TO SUPPORT RESEARCH EXPERIENCES FOR HIGH SCHOOL STUDENTS THROUGH INVESTIGATORS. NIDCR PARTICIPATES IN THE SMALL BUSINESS INNOVATION RESEARCH (SBIR) AND SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAMS. THE SBIR PROGRAM IS INTENDED TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.THE STTR PROGRAM IS INTENDED TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. EXTRAMURAL PROGRAMS ARE ACCOUNTABLE FOR THE EFFICIENT AND EFFECTIVE USE OF TAXPAYER FUNDS TO SUPPORT RESEARCH ON DENTAL, ORAL, AND CRANIOFACIAL DISEASES AND DISORDERS AND IMPROVING THE ORAL HEALTH OF ALL AMERICANS. EXTRAMURAL PROGRAMS SUPPORT RESEARCH AND RESEARCH TRAINING TO ESTABLISH THE FOUNDATION FOR SCIENTIFIC DISCOVERIES THAT INCLUDE TRANSPARENT AND RIGOROUS PLANNING, PRIORITY SETTING, CONTINUOUS AND CONSISTENT REVIEWS OF PROGRESS, AND FOCUS ON THE DEVELOPMENT OF A DIVERSE, HIGHLY SKILLED, AND NIMBLE WORKFORCE THAT CAN RAPIDLY RESPOND TO SCIENTIFIC BREAKTHROUGHS AND PUBLIC HEALTH CHALLENGES. EXTRAMURAL PROGRAMS ARE ACCOUNTABLE FOR THE EFFICIENT AND EFFECTIVE USE OF TAXPAYER FUNDS TO SUPPORT RESEARCH ON DENTAL, ORAL, AND CRANIOFACIAL DISEASES AND EMPLOY EVALUATION DOMAINS, FROM NEEDS ASSESSMENT AND STRATEGIC PLANNING TO IMPLEMENTATION AND PROCESS EVALUATION, PERFORMANCE MEASUREMENT, AND OUTCOMES AND IMPACT ANALYSIS TO EVALUATE STRATEGIC OBJECTIVES

93.121 - Oral Diseases and Disorders Research

National Institute of Dental and Craniofacial Research (NIDCR) [HHS - NIH]

Massachusetts United States

State-Wide

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)