# Elucidating Human Leukemia and T Cell Interactions within the Tumor Microenvironment

> **NIH NIH K08** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2021 · $217,528

## Abstract

Project Summary/Abstract
Leukemic relapse remains the major obstacle to successful allogeneic stem cell transplantation (allo-SCT).
Here, donor lymphocyte infusion (DLI) seeks to repair the underlying graft-versus-leukemia (GvL) effect that
drives allo-SCT efficacy. However the mechanisms driving clinical GvL outcomes remain poorly understood.
To address this challenge, Dr. Bachireddy has performed deep molecular phenotyping of both leukemia and
immune cells within the tumor microenvironment (TME) across multiple timepoints during DLI response and
resistance. He previously showed reversal of T cell exhaustion, a unique form of T cell dysfunction, during DLI
response. Using high-throughput single cell RNA sequencing (scRNA-seq), he has now identified 2 main
subtypes of exhausted T cells: terminally exhausted (TE) cells, enriched in pre-DLI responding TMEs, and
progenitor exhausted (PE) cells, expanding consistently in responders post-DLI. While these subsets are
defined in murine models of T cell exhaustion that motivated inhibitors of the PD-1 pathway, their relevance to
human leukemia, roles in immunotherapeutic response, and relationship to oncogenic pathways have not been
previously elucidated. Thus, he will test the hypothesis that specific gene regulatory networks (GRNs) (1)
define the heterogeneity within and between TE and PE subsets and, moreover, (2) are influenced by
leukemic-derived mutations and gene expression states. In Aim 1, he will determine the regulation and function
of TE and PE subsets by, first, integrating scRNA-seq data with chromatin accessibility profiles to identify
GRNs for each subset and then functionally evaluating the relative anti-leukemic efficacy of each subset (and
each GRN) in vivo. In Aim 2, he will identify leukemic-derived molecular profiles that associate with DLI
outcome and shape T/PE T cell subsets. Leukemic genomic and scRNA-seq data will be jointly analyzed to
perform in silico identification of candidate leukemic drivers of DLI outcome and T/PE T cell subsets, which will,
in turn, be functionally evaluated in vivo. These results will identify GRNs that govern, and oncogenic pathways
that shape, TE and PE T cells, revealing novel targets for modulating cancer immunity and uncovering the
molecular circuitry underpinning leukemic-immune interactions in the post-transplant TME. Dr. Bachireddy has
outlined a five-year career development plan to meet his goal of becoming an independent investigator
focused on immunotherapy in hematologic malignancies. He has assembled an Advisory Committee of
internationally recognized experts to provide scientific/career mentorship and enlisted collaborators who are
experts in computational biology, systems immunology, and functional genomics to provide experimental
advice and specific training in the field. The Dana-Farber Cancer Institute and Broad Institute of MIT and
Harvard are the ideal environments for completion of his scientific and career goals, given their outs...

## Key facts

- **NIH application ID:** 10351448
- **Project number:** 7K08CA248458-02
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** Pavan Bachireddy
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $217,528
- **Award type:** 7
- **Project period:** 2021-04-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10351448

## Citation

> US National Institutes of Health, RePORTER application 10351448, Elucidating Human Leukemia and T Cell Interactions within the Tumor Microenvironment (7K08CA248458-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10351448. Licensed CC0.

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