# Integrative approach to identify genomic features that shape the immune landscape and predict immunotherapy response in diffuse large B cell lymphoma

> **NIH NIH R01** · UNIVERSITY OF CHICAGO · 2024 · $348,827

## Abstract

PROJECT SUMMARY
Outcomes for patients with relapsed/refractory diffuse large B cell lymphoma (DLBCL) remain poor despite
recent therapeutic advances, particularly in the area of immunotherapy. Classification of solid tumor
microenvironments as immune “inflamed” or “non-inflamed” through bulk transcriptional profiling enriches for a
subset that is checkpoint blockade therapy (CBT) responsive. Conversely, the DLBCL immune landscape has
not been as well-characterized, and the extent to which immune environmental features can predict for
immunotherapy response in DLBCL patients is unknown. Given that a growing number of immunotherapies are
being explored in the relapsed/refractory DLBCL space, a deeper understanding of the DLBCL immune
landscape might uncover clues that aid in identifying patients likely to benefit from checkpoint blockade and/or
CAR T cell therapies. Additionally, growing evidence indicates that cancer cell-intrinsic alterations can
profoundly affect the tumor immune environment, which directly impacts immunotherapy sensitivity. How
recurring genetic alterations and related pathways in malignant B cells contribute to shaping the DLBCL
immune environment is unclear. Additional research is clearly needed in order to address these gaps in
knowledge. Toward that end, we incorporated curated immune- and cell-of-origin (COO)-related gene sets into
a gene set variation analysis (GSVA) on transcriptomes of 874 DLBCL specimens. Among the four clusters
that emerged (germinal center B cell (GCB) hot, GCB cold, activated B cell (ABC) hot, and ABC cold), analysis
of whole exome sequencing data revealed significantly enriched genetic alterations in each. For instance, loss-
of-function (LOF) mutations in SOCS1, a negative regulator of JAK/STAT signaling, were enriched in GCB hot
DLBCLs, suggesting these lymphomas may be particularly sensitive to IFNγ signaling and vulnerable to anti-
PD-1 therapy. Conversely, LOF alterations in TMEM30A, which regulates phosphatidylserine (PS) orientation
in the plasma membrane, were common among ABC cold DLBCLs, which may render these lymphomas
sensitive to immunotherapies that enhance macrophage phagocytosis. These observations support the central
hypothesis that lymphoma cell-intrinsic mechanisms contribute significantly to shaping unique DLBCL immune
environments, the characterization of which will identify patients who will or will not benefit from CBT or CAR T
cell therapy. The main objectives of the proposal are: 1) to determine mechanisms by which select genetic
alterations in lymphoma cells shape the DLBCL immune environment, and 2) to develop a DLBCL “immune
score” and determine its utility in identifying patients for whom PD-1 blockade or CAR T cell therapy will be
effective. The principal investigator, a physician-scientist with clinical expertise in lymphoma and a research
background in cancer immunology, is well-suited to oversee the experiments proposed in this application. In
order to execute compu...

## Key facts

- **NIH application ID:** 10830458
- **Project number:** 5R01CA273241-02
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **Principal Investigator:** Justin Paul Kline
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $348,827
- **Award type:** 5
- **Project period:** 2023-05-01 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10830458

## Citation

> US National Institutes of Health, RePORTER application 10830458, Integrative approach to identify genomic features that shape the immune landscape and predict immunotherapy response in diffuse large B cell lymphoma (5R01CA273241-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10830458. Licensed CC0.

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