Document text
Principal Investigator: John T. West
Organization: LSU HEALTH SCIENCES CENTER
Fiscal Year: 2024
Award: $528,369
Funding agency: National Cancer Institute
PROJECT SUMMARY
Epidemic Kaposi’s sarcoma (KS) is an HIV-1 associated tumor, and remains one of the highest incidence
neoplasms in sub-Saharan African men and women despite effective antiretroviral therapy (ART) programs.
The fundamental mechanism driving KS appears to be KSHV infection, but it is clear that KSHV infection alone
is insufficient for KS development since most infected individuals do not develop KS. HIV-1 co-infection or
therapeutic immune suppression induces, exacerbates, or accelerates KS disease. How HIV-1 co-infection
synergizes with KSHV to form or maintain the tumor niche is largely unexplored in tissue.
In many cancers, a clear understanding of the tumor microenvironment including the presence, antigen-
specificity and functionality of tumor-infiltrating lymphocytes (TILs) is revolutionizing therapeutic approaches.
Yet for KS we have a dearth of information about the nature of TILs and whether the tumor microenvironment
is suppressing their anti-neoplastic function in an HIV-1 dependent manner. This project seeks to rectify this
knowledge gap in a Case (HIV-1+/KS+) versus Control ((HIV-1+/KS-) design by comparatively investigating
the phenotypes and the functionality of TILs in comparison to the same cells in the peripheral immune system
and by comparing the tumor and peripheral immune cell expression patterns.
Our hypothesis is that even in the face of a detectable KSHV-reactive peripheral T cell response and effective
HIV-1 suppression, there are insufficient numbers of KSHV Ag-specifc tumor-infiltrating T lymphocytes (TILs)
and these cells are non-responsive to antigen in KS tumors. Our approach is 1) to functionally compare the
peripheral CD4 and CD8 T cell responses to KSHV and ubiquitous immunodominant antigens in KS with
differential HIV-1 disease duration; 2) to isolate, and immunophenotypically and functionally characterize KS
tumor infiltrating leukocytes; and 3) to compare the transcriptomes of TILs with autologous peripheral cells or
those from KS asymptomatic controls.
From these comparative investigations, we anticipate deriving a more robust understanding of the expression
programs and immune responsiveness of adaptive immune cells in the KS tumor niche and more complete
understanding of the role of HIV-1, immune suppression, anergy, exhaustion, and senescence in defining that
niche. This understanding will direct interventional strategies including the design of immunotherapeutics and
potentially vaccines against KS.
Terms: <AIDS><AIDS Virus><AIDS with Kaposi's sarcoma><AIDS-Related Kaposi's Sarcoma><Acceleration><Acquired Immune Deficiency><Acquired Immune Deficiency Syndrome><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome><Acquired Immunodeficiency Syndrome Virus><African><American><Anti-Cancer Agents><Antigens><Antineoplastic Agents><Antineoplastic Drugs><Antineoplastics><Autoimmune Deficiency Syndrome-Related Kaposi Sarcoma><Autologous><Automobile Driving><B blood cells><B cell><B cells><B-Cells><B-Lymphocytes><B-cell><Blood Plasma><Body Tissues><Burkitt Herpesvirus><Burkitt Lymphoma Virus><CD14><CD14 gene><CD4 Lymphocyte Count><CD4+ Cell Counts><CD4+ Counts><CD68 antigen><CD8><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><CD8B><CD8B1><CD8B1 gene><CMV><CSIF><CSIF-10><CXCL9><CXCL9 gene><Cancer Drug><Cancers><Causality><Cd68><Cell Body><Cells><Chemoattractants><Chemotactic Factors><Chemotaxins><Collaborations><Communities><Cytokine Synthesis Inhibitory Factor><Cytomegalovirus><Data><Defect><Dermatologic biopsy><Development><Diagnosis><Disease><Disorder><EB virus><EBV><Effector Cell><Environment><Epidemic Kaposi's Sarcoma><Epstein Barr Virus><Etiology><Evaluation><Expression Profiling><Failure><Grippe><HCMV><HHV-4><HHV-8><HHV4><HHV8><HIV><HIV-1><HIV-I><HIV1><Herpes infection><Herpesviridae Infections><Herpesviridae disease><Herpesvirus Infections><Human Herpesvirus 4><Human Herpesvirus 8><Human Immunodeficiency Virus Type 1><Human Immunodeficiency Viruses><Human immunodeficiency virus 1><Humig><IL-10><IL10><IL10A><Iatrogenesis><Immune><Immune system><Immunes><Immunity><Immunochemical Immunologic><Immunodominant Antigens><Immunologic><Immunologic Subtyping><Immunological><Immunologically><Immunologics><Immunophenotyping><Immunosuppression><Immunosuppression Effect><Immunosuppressive Effect><Immunotherapeutic agent><Incidence><Individual><Infectious Mononucleosis Virus><Infiltration><Inflammatory><Influenza><Interleukin 10 Precursor><Interleukin-10><Intervention><Intervention Strategies><Investigation><KSHV><Kaposi Sarcoma><Kaposi Sarcoma-Associated Herpes Virus><Kaposi Sarcoma-Associated Herpesvirus><Kaposi sarcoma associated virus><Kaposi sarcoma herpes virus><Kaposi's Sarcoma><Kaposi's Sarcoma Epidemic Type><Kaposi's sarcoma (KS)-associated herpesvirus><Knowledge><LAV-HTLV-III><LYT3><Leucocytic infiltrate><Lymphadenopathy-Associated Virus><MIG Gene><Macrophage><Malignant Neoplasms><Malignant Tumor><Memory><Molecular><Multiple Hemorrhagic Sarcoma><Mφ><Nature><Neoplasms><Neoplastic Disease Chemotherapeutic Agents><Northern Rhodesia><PBMC><Patients><Pattern><Peptides><Peripheral><Peripheral Blood Mononuclear Cell><Phenotype><Plasma><Plasma Serum><Population><Process><RNA Seq><RNA sequencing><RNAseq><Resected><Reticuloendothelial System, Serum, Plasma><Role><SCYB9><Salivary Gland Viruses><Sorting><Specificity><Suspension substance><Suspensions><T cell differentiation><T cell response><T-Cells><T-Lymphocyte><T4 Lymphocyte Count><T8 Cells><T8 Lymphocytes><Teaching Hospitals><Testing><Therapeutic><Tissues><Tumor Tissue><Tumor-Infiltrating Lymphocytes><Tumor-Specific Treatment Agents><Universities><Vaccines><Viral><Virus-HHV8><Virus-HIV><Woman><Zambia><anergy><anti-cancer drug><antiretroviral therapy><antiretroviral treatment><cancer infiltrating T cells><cancer microenvironment><causation><check point inhibition><checkpoint inhibition><co-infection><coinfection><comparative><complement chemotactic factor><crg-10><cutaneous biopsy><cytokine><cytomegalovirus group><design><designing><developmental><disease causation><disease duration><disease length><driving><exhaustion><global gene expression><global transcription profile><iatrogenic><iatrogenically><iatrogenicity><illness length><immune check point inhibition><immune checkpoint inhibition><immune drugs><immune reconstitution><immune suppression><immune suppressive activity><immune suppressive function><immune-based therapeutics><immunogen><immunologic therapeutics><immunophenotype><immunosuppressive activity><immunosuppressive function><immunosuppressive response><immunotherapeutics><immunotherapy agent><interventional strategy><kaposi's sarcoma herpesvirus><kaposi's sarcoma-associated human herpesvirus><malignancy><men><neoplasia><neoplasm/cancer><neoplastic><neoplastic growth><patient stratification><programs><response><senescence><senescent><skin biopsy><social role><stratified patient><synergism><thymus derived lymphocyte><transcriptome><transcriptome sequencing><transcriptomic sequencing><tumor><tumor infiltrating T cells><tumor microenvironment>