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Principal Investigator: Jeffrey J. Ishizuka
Organization: YALE UNIVERSITY
Fiscal Year: 2024
Award: $212,878
Funding agency: National Cancer Institute
PROJECT SUMMARY:
Immune checkpoint inhibition of the PD-1/PD-L1 pathway has demonstrated dramatic and durable
clinical benefit for patients in many cancer types and is increasingly being incorporated into standard of care
treatment regimens. However, in most tumor types, this strategy is effective only for a minority of patients. As
such, there is an urgent need for novel therapeutic approaches to potentiate immune checkpoint blockade and
increase the proportion of patients who benefit from it. We recently used in vivo CRISPR screening in
transplantable mouse tumor models treated with antibodies targeting PD-1 to identify the RNA editing enzyme,
ADAR1, as a novel target for combination immunotherapy. In a manuscript published in Nature, we showed
that loss of ADAR1 can overcome two of the most common and challenging mechanisms of resistance to
immunotherapy: a lack of infiltration of anti-tumor immune cells in the tumor microenvironment and the loss of
antigen presentation by the class I major histocompatibility complex on tumor cells. However, the mechanisms
by which loss of ADAR1 achieves these therapeutic goals are unclear. In Aim 1 and Aim 2 of this grant, I
propose to define these mechanisms and to elaborate general principles by which resistance to
immunotherapy can be overcome. More broadly, the identification of ADAR1 as a target for improving
responses to immunotherapy suggests that targeting other enzymes that are associated with a similar auto-
inflammatory phenotype in humans could similarly benefit patients treated with immune checkpoint blockade. I
propose to test this hypothesis in Aim 3 of this grant. If successful, these results will provide a mechanistic
paradigm for overcoming resistance to immunotherapy and identify novel drug targets that trigger a similar
mechanism.
I am currently a Clinical Fellow in Medical Oncology in the Dana-Farber/Partners CancerCare
Hematology and Oncology Fellowship Program. Over 85% of my time is devoted to my ongoing research
under the mentorship of Dr. Matthew Meyerson (DFCI, Broad Institute) and Dr. Arlene Sharpe (Harvard
Medical School). The remainder of my time is devoted to clinical practice and training at the Dana-Farber
Cancer Institute, primarily in thoracic and gynecologic medical oncology. My goal is to successfully transition
from senior fellow to research instructor and ultimately to an independent investigator in a tenure-track
position. I am applying for the K08 Mentored Clinical Scientist Research Career Development Award to provide
the necessary training and funding to achieve this goal. Under the mentorship of Drs. Meyerson and Sharpe,
and the guidance of my advisory committee (Drs. Golub, Freeman, Hur and Barbie), I will access the
necessary resources and training to develop a successful, independent research program over the funding
period of the award.
Terms: <ADAR1><Advisory Committees><Aicardi Goutieres syndrome><Anti-viral Response><Antibodies><Antigen Presentation><Award><B cell differentiation factor><B cell stimulating factor 2><B-Cell Differentiation Factor><B-Cell Differentiation Factor-2><B-Cell Stimulatory Factor-2><BCDF><BSF-2><BSF2><CCL25><CCL25 gene><CCL5><CREE ENCEPHALITIS><CRG-2><CRISPR approach><CRISPR based approach><CRISPR editing screen><CRISPR method><CRISPR methodology><CRISPR screen><CRISPR technique><CRISPR technology><CRISPR tools><CRISPR-CAS-9><CRISPR-based method><CRISPR-based screen><CRISPR-based technique><CRISPR-based technology><CRISPR-based tool><CRISPR/CAS approach><CRISPR/Cas method><CRISPR/Cas technology><CRISPR/Cas9><CRISPR/Cas9 screen><CRISPR/Cas9 technology><CXCL10><CXCL10 gene><CXCL11><CXCL11 gene><Cancers><Career Development Awards><Career Development Awards and Programs><Career Development Programs K-Series><Cas nuclease technology><Cell Line><CellLine><Chemicals><Chemokine (C-C Motif) Ligand 5><Chemokine, CC Motif, Ligand 25><Chemotactic Cytokines><Chest><Clinical><Clustered Regularly Interspaced Short Palindromic Repeats approach><Clustered Regularly Interspaced Short Palindromic Repeats method><Clustered Regularly Interspaced Short Palindromic Repeats methodology><Clustered Regularly Interspaced Short Palindromic Repeats technique><Clustered Regularly Interspaced Short Palindromic Repeats technology><Combination immunotherapy><Complex><Cytotoxic cell><D17S136E><DF/HCC><Dana-Farber Cancer Institute><Disease><Disorder><Double-Stranded RNA><Drug Targeting><Effectiveness><Encephalopathy with intracranial calcification and chronic lymphocytosis of cerebrospinal fluid><Encephalopathy, familial infantile, with calcification of basal ganglia and chronic cerebrospinal fluid lymphocytosis><Enzyme Gene><Enzymes><Event><Fellowship Program><Funding><Future><Genes><Genetic><Genetic Alteration><Genetic Change><Genetic defect><Goals><Grant><Gynecologic><H174><HPGF><Hematology><Hepatocyte-Stimulating Factor><Histocompatibility Complex><Histocompatibility Complices><Homologous Chemotactic Cytokines><Human><Hybridoma Growth Factor><I-TAC><I-antigen><IFI10><IFN><IFN-beta 2><IFNB2><IL-6><IL6 Protein><INP10><IP-10><IP-9><IP9><Immune infiltrates><Immune mediated therapy><Immune response><Immune system><Immunologic Technics><Immunologic Techniques><Immunological Technics><Immunological Techniques><Immunological response><Immunologically Directed Therapy><Immunotherapy><Infiltration><Inflammation><Inflammatory><Innate Immunity><Intercrines><Interferons><Interleukin-6><Investigators><K lymphocyte><K-Awards><K-Series Research Career Programs><Knock-out><Knockout><Lead><MGC17164><MGI-2><MOB-1><Major Histocompatibility Complex><Major Histocompatibility Complices><Malignant Neoplasms><Malignant Tumor><Manuscripts><Mediating><Mediator><Medical Oncology><Mentors><Mentorship><Mice><Mice Mammals><Minority><Modeling><Modern Man><Murine><Mus><Mutation><Myeloid Differentiation-Inducing Protein><NK Cells><Native Immunity><Natural Immunity><Natural Killer Cells><Nature><Neoplasm Transplantation><Non-Specific Immunity><Nonspecific Immunity><Nucleic Acids><Oncology><Oncology Cancer><PD 1><PD-1><PD-1/PD-L1><PD-1/PDL1><PD-L1 pathway><PD1><PD1-PD-L1><PD1/PD-L1><PD1/PDL1><PDL1 pathway><Patients><Pb element><Phenocopy><Phenotype><Plasmacytoma Growth Factor><Position><Positioning Attribute><Proteins><Publishing><RANTES><RNA Editing><RNA, Messenger, Editing><Research><Research Career Program><Research Personnel><Research Resources><Researchers><Resistance><Resources><SCYA25><SCYA5><SCYB10><SCYB11><SCYB9B><SIS cytokines><SIS delta><SIS-delta><SISd><Scientist><Small Inducible Cytokine A5><Small Inducible Cytokine Subfamily A, Member 25><Strains Cell Lines><System><T-Cell RANTES Protein><T-Cell Specific Protein p288><TCP228><TECK><TREX1 protein><Task Forces><Tcr region expressed 1 protein><Testing><Therapeutic><Thorace><Thoracic><Thorax><Thymus-Expressed Chemokine><Time><Training><Transplantation><Treatment Protocols><Treatment Regimen><Treatment Schedule><Tumor Cell><Tumor-infiltrating immune cells><Work><advisory team><anti-cancer immunotherapy><anti-viral immunity><anticancer immunotherapy><antiviral immunity><autoinflammatory><b-R1><cancer care><cancer immunotherapy><cancer microenvironment><cancer type><check point blockade><check point inhibition><checkpoint blockade><checkpoint inhibition><chemoattractant cytokine><chemokine><clinical practice><clinical training><clustered regularly interspaced short palindromic repeats screen><combinatorial immunotherapy><cultured cell line><cytokine><dsRNA><dual immunotherapy><gIP-10><genetic approach><genetic strategy><genome editing><genome mutation><genomic editing><heavy metal Pb><heavy metal lead><host response><immune cell infiltrate><immune cell infiltration of tumors><immune cells infiltrating the tumor><immune cells that infiltrate the tumor><immune check point><immune check point blockade><immune check point inhibition><immune checkpoint><immune checkpoint blockade><immune checkpoint inhibition><immune microenvironment><immune system response><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based cancer therapies><immune-based therapies><immune-based treatments><immunecheckpoint><immuno therapy><immunoresponse><immunosuppressive microenvironment><immunosuppressive tumor microenvironment><immunotherapy for cancer><immunotherapy of cancer><improved><in vivo><in vivo Model><infiltration of tumors by immune cells><innate check point><innate checkpoint><innate immune check point><innate immune checkpoint><innate immunity checkpoint><instructor><interferon beta 2><intratumoral immune cell><intratumoral immune infiltrate><malignancy><medical college><medical schools><microcephaly-chorioretinopathy syndrome><neoplasm/cancer><neoplastic cell><new approaches><new drug class><new drug target><new druggable target><new pharmacotherapy target><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapeutic target><new therapy approaches><new therapy target><new treatment approach><new treatment strategy><novel><novel approaches><novel drug class><novel drug target><novel druggable target><novel pharmacotherapy target><novel strategies><novel strategy><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapeutic target><novel therapy approach><novel therapy target><nucleic acid inhibitor><overexpress><overexpression><programmed cell death 1><programmed cell death ligand 1 pathway><programmed cell death protein 1><programmed cell death protein ligand 1 pathway><programmed death 1><programs><pseudotoxoplasmosis syndrome><recruit><resistance mechanism><resistant><resistant mechanism><response><response biomarker><response markers><school of medicine><sle2><standard of care><success><systemic lupus erythematosus susceptibility 2><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><tenure process><tenure track><therapeutic agent development><therapeutic development><tool><transplant><tumor><tumor immune cell><tumor immune infiltrate><tumor immune microenvironment><tumor infiltration of immune cells><tumor microenvironment><tumor transplant><tumor transplantation><tumor-immune system interactions>