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Principal Investigator: Kavitha Yaddanapudi
Organization: UNIVERSITY OF LOUISVILLE
Fiscal Year: 2024
Award: $335,530
Funding agency: National Cancer Institute
Lung cancer kills more people than any other type of cancer, including more than 130,000 people each year in
the United States. Non-small cell lung cancer (NSCLC) is the most common subtype (82% of all lung cancers)
and can arise from squamous or non-squamous lung epithelial cells. Combination treatment with immunotherapy
(i.e., monoclonal antibodies targeted to PD-1 or PD-L1) plus concurrent chemotherapy (usually including cisplatin
or carboplatin) is now part of the standard of care for many patients with NSCLC. Although in lab-based studies,
chemotherapy has some effects that are expected to enhance the efficacy of immunotherapies, whether
chemotherapy can also have paradoxical negative effects that diminish immunotherapy efficacy is not well
understood at present. Based on our preliminary data, we propose to investigate how cisplatin, a chemotherapy
commonly used to treat NSCLC, creates an immunosuppressive tumor microenvironment (TME) that limits the
anti-tumor activity of anti-PD-1 immunotherapy. Specifically, we hypothesize the following steps: (a) cisplatin
induces prostaglandin E2 (PGE2) production in tumor cells; (b) PGE2 leads to upregulation of CD73 enzyme on
the surface of monocytic myeloid-derived suppressor cells (M-MDSCs); (c) CD73 catalyzes the production of
extracellular adenosine from AMP (derived from ATP released from dying cells); and (d) adenosine inhibits the
activation of effector T cells within the tumor microenvironment (TME) and thus limits the efficacy of chemo-
immunotherapy. Furthermore, we propose a novel therapeutic strategy for overcoming this adenosine-mediated
immunosuppression and sensitizing tumors to chemo-immunotherapy, whereby co-treatment with recombinant
polyethylene glycol-conjugated adenosine deaminase enzyme (PEG-ADA) will convert immunosuppressive
adenosine into immunostimulatory inosine. In Specific Aim 1 of this project, we will test our predictions about the
key cellular and molecular players in this pathway, including cisplatin-induced PGE2 secretion, CD73 expression
on M-MDSC, adenosine production and suppression of anti-tumoral T cell activity. We will use a variety of in vivo
systems that provide a faithful representation of human NSCLC, including an orthotopic murine lung cancer
model and humanized mice with patient-derived xenografts (PDX). In Specific Aim 2, we will test the
effectiveness of selectively deleting CD73 in M-MDSCs or co-treating with PEG-ADA as approaches to increase
the anti-tumor/immunostimulatory activities of chemo-immunotherapy (anti-PD-1 + cisplatin) in transgenic mouse
models of non-squamous and squamous NSCLC. We will also examine tumor samples from NSCLC patients
who have progressed on anti-PD-1/chemotherapy for correlative evidence of this novel mechanism. Completion
of these aims will identify novel and actionable immunosuppressive mechanisms that mediate relapse and
therapeutic resistance in metastatic NSCLC patients. Our studies will establish adding PEG-ADA (a drug that is
FDA-approved for a non-cancer indication) to standard chemo-immunotherapy as a promising strategy that can
be quickly translated into improved NSCLC treatment regimens.
Terms: <Address><Adenosine><Adenosine Aminohydrolase><Attenuated><B7-H1><B7H1><Blood monocyte><CBDCA><CD274><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><CDDP><COX-2><COX2><Cancer Model><Cancer Patient><Cancer Treatment><CancerModel><Carboplatin><Carboplatino><Cell Body><Cell Function><Cell Physiology><Cell Process><Cells><Cellular Function><Cellular Physiology><Cellular Process><Checkpoint inhibitor><Cis-diammine-dichloroplatinum><Cis-diamminedichloridoplatinum><Cis-diamminedichloro Platinum (II)><Cis-dichloroammine Platinum (II)><Cis-platinous Diamine Dichloride><Cis-platinum II><Cis-platinum II Diamine Dichloride><Cisplatin><Cisplatina><Cisplatinum><Clinical><Clinical Treatment Moab><Combination immunotherapy><Combined Modality Therapy><Cysplatyna><Cytotoxic agent><Cytotoxic drug><D-Glucose><DA-nucleotidase><Data><Dextrose><Dichlorodiammineplatinum><Dinoprostone><Disease><Disorder><Drugs><Effectiveness><Energy-Generating Resources><Enzyme Gene><Enzymes><Epithelial Cells><Eragrostis><FDA approved><Generations><Glucose><Health><Heterograft><Heterologous Transplantation><Human><Immune><Immune Evasion><Immune checkpoint inhibitor><Immune mediated therapy><Immune response><Immune system><Immunes><Immuno-Chemotherapy><Immunochemotherapy><Immunological response><Immunologically Directed Therapy><Immunosuppression><Immunosuppression Effect><Immunosuppressive Effect><Immunotherapeutic agent><Immunotherapy><Inosine><KRAS(G12D)><KRASG12D><Life><Lung><Lung Respiratory System><Macrogols><Malignant Cell><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Tumor of the Lung><Malignant neoplasm of lung><Marrow monocyte><Mediating><Medication><Metabolic><Mice><Mice Mammals><Modeling><Modern Man><Molecular><Monoclonal Antibodies><Multimodal Therapy><Multimodal Treatment><Murine><Mus><Myeloid Cells><Myeloid-derived suppressor cells><NSCLC><NSCLC - Non-Small Cell Lung Cancer><Non-Small Cell Lung Cancer><Non-Small-Cell Lung Carcinoma><Nucleotidases><Nutrient><Outcome><PD 1><PD-1><PD-1 antibody><PD-L1><PD1><PD1 antibody><PDL-1><PDL1><PDX model><PGE2><PGE2 alpha><PGE2alpha><PGHS-2><PHS-2><PTGS2><PTGS2 gene><Paracrine Communication><Paracrine Signaling><Pathway interactions><Patient derived xenograft><Patients><Persons><Peyrone's Chloride><Peyrone's Salt><Pharmaceutical Preparations><Platinum Diamminodichloride><Polyethylene Glycols><Polyethylene Oxide><Polyethyleneoxide><Polyoxyethylenes><Polyunsaturated Fatty Acids><Production><Programmed Cell Death 1 Ligand 1><Programmed Death Ligand 1><Prostaglandin E2><Prostaglandin E2 alpha><Prostaglandin E2alpha><Pulmonary Cancer><Pulmonary malignant Neoplasm><Purine Nucleosides><Recombinants><Relapse><Resistance><Risk><Sampling><Signal Induction><Signal Pathway><Subcellular Process><Surface><System><T-Cells><T-Lymphocyte><T8 Cells><T8 Lymphocytes><Teff><Teff cell><Testing><Therapeutic><Transgenic Mice><Translating><Treatment Failure><Treatment Protocols><Treatment Regimen><Treatment Schedule><Tumor Cell><Tumor Immunity><United States><Up-Regulation><Upregulation><Xenograft><Xenograft procedure><Xenotransplantation><aPD-1><aPD1><adenosine deaminase><anti programmed cell death 1><anti-PD-1><anti-PD-1 Ab><anti-PD-1 antibodies><anti-PD-1 monoclonal antibodies><anti-PD1><anti-PD1 Ab><anti-PD1 antibodies><anti-PD1 monoclonal antibodies><anti-cancer therapy><anti-programmed cell death protein 1><anti-programmed cell death protein 1 antibodies><anti-programmed death-1 antibody><anti-tumor immunity><antiPD-1><antiPD1><antitumor immunity><attenuate><attenuates><cancer cell><cancer immunity><cancer microenvironment><cancer therapy><cancer type><cancer-directed therapy><chemo-immuno therapy><chemoimmunotherapy><chemotherapy><cis dichlorodiammineplatinum><cis platinum compound><cis-Diaminedichloroplatinum><cis-Diamminedichloroplatinum><cis-Diamminedichloroplatinum(II)><cis-Dichlorodiammineplatinum(II)><cis-Platinum><clinical relevance><clinically relevant><combination therapy><combinatorial immunotherapy><combined modality treatment><combined treatment><cytosolic deoxyribonucleotide-activated nucleotidase><deoxyinosine-activated nucleotidase><drug/agent><dual immunotherapy><effectiveness testing><effector T cell><energy source><extracellular><hCOX-2><host response><human disease><humanized mice><humanized mouse><immune check point inhibitor><immune drugs><immune evasive><immune microenvironment><immune suppression><immune suppressive activity><immune suppressive function><immune system response><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based therapeutics><immune-based therapies><immune-based treatments><immuno therapy><immunogenic apoptosis><immunogenic cell death><immunologic therapeutics><immunoresponse><immunosuppressive activity><immunosuppressive function><immunosuppressive microenvironment><immunosuppressive myeloid cells><immunosuppressive response><immunosuppressive tumor microenvironment><immunotherapeutics><immunotherapy agent><improved><in vivo><innovate><innovation><innovative><lung cancer><mAbs><monoclonal Abs><monocyte><mortality><mouse model><multi-modal therapy><multi-modal treatment><murine model><myeloid suppressor cells><myeloid-derived suppressive cells><neoplastic cell><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><new treatment approach><new treatment strategy><novel><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapy approach><nucleotidase><nucleotide phosphohydrolase><pathway><patient derived xenograft model><programmed cell death 1><programmed cell death ligand 1><programmed cell death protein 1><programmed cell death protein ligand 1><programmed death 1><protein death-ligand 1><pulmonary><randomized, clinical trials><resistance to therapy><resistant><resistant to therapy><response><sle2><standard of care><suppressive myeloid cells><systemic lupus erythematosus susceptibility 2><therapeutic resistance><therapy failure><therapy resistant><thymus derived lymphocyte><treatment resistance><tumor><tumor ablation><tumor immune microenvironment><tumor microenvironment><tumor-immune system interactions><xeno-transplant><xeno-transplantation><αPD-1><αPD1>