Document text
Principal Investigator: Alexander Huang
Organization: UNIVERSITY OF PENNSYLVANIA
Fiscal Year: 2024
Award: $536,024
Funding agency: National Cancer Institute
Project Summary
Anti-PD-1 therapy reinvigorates exhausted CD8 T cells, which can lead to complete tumor eradication as early
as 3 weeks. Yet, despite robust T cell reinvigoration in >78% of patients, less than 40% are cured. The goal of
this proposal is to understand why robust reinvigoration of exhausted CD8 T cells by αPD-1 therapy does not
necessarily translate to clinical efficacy.
Exhausted CD8 T cells (TEX) are a major cell type responding to PD-1 blockade. We and others have shown
that αPD-1 therapy (αPD-1) reinvigorates exhausted CD8 T cells, as defined by enhanced proliferation and
cytokine production. TEX are heterogeneous with progenitor and terminally differentiated TEX that have different
roles in anti-tumor immune responses. Progenitor TEX (ProgEX) replenish terminally differentiated TEX (TermEX),
which in turn provide anti-tumor activity. Thus, similar to stem cells, ProgEX represent a reservoir for CD8 T cell
responses against the tumor. Importantly, it is the ProgEX, rather than TermEX, that respond to αPD-1 and
almost exclusively contribute to the early burst of CD8 T cell reinvigoration. Reinvigoration of TEX results in
accelerated differentiation of ProgEX to TermEX, resulting in a numerically greater pool of TermEX and improved
tumor control. However, at the same time, the accelerated differentiation induced by αPD-1 places increased
stress on ProgEX homeostasis. This raises the possibility that a ProgEX niche is key for providing the cells and
signals necessary to prevent the depletion of ProgEX, and may prove crucial for the efficacy of PD-1 blockade.
Our central hypothesis is that depletion of ProgEX after αPD-1 impairs clinical efficacy and that a tumor-
associated niche is important in maintaining the pool of ProgEX. In Aim 1, we will test the hypothesis that
αPD-1 results in enhanced differentiation of ProgEX and that that depletion of ProgEX is associated with clinical
progression. We will use combinatorial tetramers and single cell RNA+TCR sequencing to understand how
αPD-1 alters the pool of melanoma-specific ProgEX, and how the size of ProgEX pool in turn, impacts the clinical
efficacy of αPD-1. In Aim 2, we test the hypothesis that tertiary lymphoid structures serve as a tumor-
associated niche for ProgEX, and that increased number or size of ProgEX niches after αPD-1 is associated with
the preservation of ProgEX and clinical efficacy. We will use multiparameter immunofluorescence and spatial
transcriptomics to define the cellular composition of the ProgEX niche, the transcriptional circuits utilized by
ProgEX in the niche, and the importance of the ProgEX niche in preserving the pool of ProgEX.
Terms: <Acceleration><Address><After Care><After-Treatment><Aftercare><Antigens><Autoregulation><Biometrics><Biometry><Biostatistics><Blood><Blood Reticuloendothelial System><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><Cancer Patient><Cancers><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Chronic><Clinical><Clinical Trials><Clone Cells><Collection><Data><Dendritic Cells><Development><Dose><Ectopic lymphoid organ><Ectopic lymphoid structure><Equilibrium><Failure><Frequencies><Gene Transcription><Genetic Transcription><Goals><Homeostasis><Human><Immunofluorescence><Immunofluorescence Immunologic><Immunology><Impairment><Induction Therapy><Inflammation><Intracellular Communication and Signaling><Investigators><Knowledge><Malignant Melanoma><Malignant Neoplasms><Malignant Tumor><Melanoma><Melanoma Tumor><Melanoma patient><Minority><Modeling><Modern Man><NEOADJ><Neoadjuvant><Neoadjuvant Therapy><Neoadjuvant Treatment><Non-Polyadenylated RNA><Outcome><PD-1 antibody therapy><PD-1 blockade><PD-1 therapy><PD1 antibody therapy><PD1 based treatment><PD1 blockade><Participant><Pathology><Patients><Physiological Homeostasis><Population><Position><Positioning Attribute><Production><Progenitor Cells><Proliferating><RNA><RNA Expression><RNA Gene Products><Research Personnel><Researchers><Resolution><Ribonucleic Acid><Role><Signal Transduction><Signal Transduction Systems><Signaling><Stress><Structure><Study Subject><Supporting Cell><T cell differentiation><T cell infiltration><T cell receptor repertoire sequencing><T cell receptor sequencing><T cell response><T-Cell Depletion><T-Cell Subsets><T-Cells><T-Lymphocyte><T-Lymphocyte Subsets><T-cell depletion therapy><T-lymphocyte depletion therapy><T8 Cells><T8 Lymphocytes><TCR repertoire sequencing><TCR sequencing><TCR-seq><TCRseq><Tertiary lymphoid structure><Testing><Time><Transcription><Translating><Tumor Cell><Tumor growth in melanoma><Veiled Cells><Viral Cancer><Viral Diseases><Virus Diseases><aPD-1><aPD-1 therapy><aPD-1 treatment><aPD1><aPD1 therapy><aPD1 treatment><anti programmed cell death 1><anti-PD-1><anti-PD-1 blockade><anti-PD-1 therapy><anti-PD-1 treatment><anti-PD1><anti-PD1 blockade><anti-PD1 therapy><anti-PD1 treatment><anti-programmed cell death 1 therapy><anti-programmed cell death protein 1><anti-programmed cell death protein 1 therapy><anti-tumor immune response><antiPD-1><antiPD1><balance><balance function><biological signal transduction><cell type><check point blockade><checkpoint blockade><clinical efficacy><clinical relevance><clinically relevant><combinatorial><cytokine><developmental><exhaust><experience><human progenitor><human stem cells><immune check point blockade><immune checkpoint blockade><immunogen><improved><induction therapies><lymphoid structures><malignancy><neoplasm/cancer><neoplastic cell><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><post treatment><pre-clinical study><preclinical study><preservation><prevent><preventing><progenitor><progenitor cell differentiation><progenitor cell niche><progenitor differentiation><progenitor niche><programmed cell death protein 1 therapy><programs><resolutions><response><self-renew><self-renewal><social role><stem and progenitor cell niche><stem and progenitor differentiation><stem cell differentiation><stem cell niche><stem cells><tertiary lymphoid organ><thymus derived lymphocyte><transcriptomics><tumor><tumor eradication><viral infection><virus infection><virus-induced disease><αPD-1><αPD1>