# Role of the stromal microenvironment in B-cell lymphoma progression and immune escape

> **NIH NIH R01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2022 · $529,121

## Abstract

PROJECT SUMMARY/ABSTRACT
This project focus in the biology of diffuse large B-cell lymphoma (DLBCL) that are common aggressive
malignancies with a curability rate of 65% despite intensive chemoimmunotherapy. DLBCLs display an array of
genetic alterations, that define molecular subtypes, and strong dependence on the microenvironment for survival.
We hypothesize that reprogramming of the stromal microenvironment is critical for the oncogenicity of hallmark
mutations that mediate lymphoma progression and immune evasion. We propose to elucidate the roles of the
cancer-associated fibroblasts (CAF) and extracellular matrix (ECM) components of the lymphoma
microenvironment to identify therapeutic vulnerabilities. CAFs are derived from healthy fibroblasts that have been
reprogrammed by cancer cells into a novel biological entity. Our long-term goal is to therapeutically exploit
reprogrammed CAFs with consideration of genetically-defined DLBCLs. For this reason, it is critical to elucidate
the mechanisms involved in CAF reprogramming. Not all CAFs are reprogrammed in the same way. Moreover,
rather than a terminal effect, CAF reprogramming as a transcriptionally dynamic process that allows the
establishment of a variety of adaptive phenotypes. Our preliminary data suggest the activation of “shared” and
“private” pathways in the reprogramming of CAFs. We specifically identify and studied the role of HSF1, one of
the “shared” transcription factors in CAFs. CAFs without HSF1 failed to produce an ECM with the biochemical
composition and mechanical properties required for lymphoma progression. Concomitantly, lack of HSF1 in the
TME allowed the establishment of an effective lymphoma immune response leading to tumor eradication. We
plan to test our central hypothesis and accomplish the objective of this application by pursuing these specific
aims: Aim 1. Elucidate mechanisms of CAFs reprogramming that sustain genetically diverse DLBCLs:
We will identify CAFs sub-populations and ECM composition in genetic DLBCL subtypes; and identify molecular
pathways and reprogramming factors across and within CAFs sub-populations using HSF1 as lead effector. Aim
2. Elucidate the role of CAFs in functionalizing the ECM for immune evasion. We will characterize
biomechanical and biochemical constraints imposed by CAFs to an effective lymphoma immunity. Aim 3.
Determine the therapeutic impact of targeting CAFs in genetic DLBCL subtypes. We will determine the
anti-lymphoma effect of co-targeting CAFs and lymphoma cells in molecularly-defined pre-clinical DLBCL murine
models. The studies that we propose will provide significant insights on the mechanisms of stromal TME
reprogramming for the establishment of genetically defined DLBCLs and will contribute towards development of
novel therapeutic strategies focused on targeting the stromal TME in these entities to increase curability.

## Key facts

- **NIH application ID:** 10308482
- **Project number:** 5R01CA242069-03
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Leandro C Cerchietti
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $529,121
- **Award type:** 5
- **Project period:** 2019-12-01 → 2024-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10308482

## Citation

> US National Institutes of Health, RePORTER application 10308482, Role of the stromal microenvironment in B-cell lymphoma progression and immune escape (5R01CA242069-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10308482. Licensed CC0.

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