# Towards targeting the lymphoma microenvironment

> **NIH NIH R35** · SLOAN-KETTERING INST CAN RESEARCH · 2022 · $1,040,760

## Abstract

Towards Targeting the Follicular Lymphoma Microenvironment
Follicular lymphoma (FL) is the second most common and still incurable form of B cell
lymphoma. FL is a slow growing cancer that shows a unique dependence on a
supportive microenvironment. The supportive niche also affects FL therapies. For
example, inhibitors of BTK, PI3K, or BCL2 show exciting activity against aggressive
lymphomas and chronic leukemia, but they have little activity against indolent FLs. We
speculate that the FL microenvironment protects and sustains the malignant B cells and
contributes to FL development, progression, and resistance to therapy. Conversely, we
propose that disrupting interactions in the FL niche will be especially effective against
FL. Our hypothesis is based on prior work by others and our own work on immune
receptor mutations in FL (e.g. TNFSRF14 and EphA7) have revealed cell-cell
interactions as key drivers and sustainers of FL biology.
My lab has made major contributions to our understanding of the biology and genetics of
FL. We built an accurate mouse model of FL and we and others have used this model to
interpret the biological function of the most common FL drivers. For example, we
reported on the role of epigenetic driver mutations in KMT2D, CREBBP, EZH2, we
investigated FL cell metabolism, cell cycle control, aberrant mRNA translation, and the
outstanding importance of immune receptors (e.g. TNFSRF14, b2M, EphA7) in FL
biology. This work has been reported in an extensive series of high-impact publications.
It has also led to several patent filings that protect experimental lymphoma therapies.
We now propose a systematic assessment of the cellular composition of the FL
microenvironment using cutting edge single-cell RNA sequencing on murine and human
FLs. We want to understand how tumor genotype, indolent versus transformed disease
stage, and therapy (esp. checkpoint inhibition) shapes the FL niche. We use single cell
data to formulate specific hypotheses concerning cell-cell interactions and we use
genetic and molecular biology tools to explore underlying mechanisms. Our goal is to
identify opportunities to disrupt the supportive niche and to exploit this for new therapies.
We have already had some success in this regard, and we engineered bi-functional
antibodies and modified CAR-T cells that target interactions between malignant B cells
and supportive niche elements.
!

## Key facts

- **NIH application ID:** 10469578
- **Project number:** 5R35CA252982-03
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** Hans-Guido Wendel
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $1,040,760
- **Award type:** 5
- **Project period:** 2020-09-01 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10469578

## Citation

> US National Institutes of Health, RePORTER application 10469578, Towards targeting the lymphoma microenvironment (5R35CA252982-03). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10469578. Licensed CC0.

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