# A Novel Mechanism of Immune Escape by B-cell Lymphoma

> **NIH VA I01** · RALPH H JOHNSON VA MEDICAL CENTER · 2024 · —

## Abstract

Abstract
Hematological malignancy is noted as a presumptive disease related to ionizing radiation exposure during
military service and has been associated with exposure to toxic contaminants. Lymphoid malignancies such
as lymphoma and leukemia often compromise host defense by developing mechanisms to evade immune
surveillance. Effective tumor immune responses involve the activation and maintenance of tumor-specific
CD8+ HLA class I-restricted cytotoxic T cells (CTL) and tumor-specific CD4+ class II-restricted helper T cells.
However, many B-cell lymphomas cannot optimally present antigens (Ags) via the HLA class I pathway, which
contributes to their escaping immune recognition from tumor-specific CD8+ T cells. We have recently shown
that B-cell lymphoma-induced stimulation of CD4+ T cells is also impaired however, the mechanisms involved
remain unknown. Preliminary and published data presented here indicate that B-cell lymphomas shed a
49kDa Fc Receptor Like A (FCRLA) molecule which suppresses the ability of professional antigen presenting
cells (APCs) to stimulate CD4+ T cells via the HLA class II pathway. We hypothesize that the shedding of
this FCRLA molecule plays a key role in B-cell lymphoma-mediated immune suppression and that
blockade of this molecule may restore T cell recognition of this class of malignancies. In support, we
show that a novel 49kDa FCRLA molecule secreted by B-cell tumors binds to HLA class II protein and disrupts
functional Ag presentation by professional APCs. Second, higher levels of FCRLA were detected in B-cell
lymphoma patients, which correlated with poor patient outcome. Third, knockdown of FCRLA by shRNA
restored functional HLA class II-Ag presentation by B-cell lymphomas to T cells. Fourth, FCRLA antibody
therapy augmented CD4+ T cell recognition of B-cell lymphoma in vitro and in vivo. These data provide a solid
foundation for our overall goal of elucidating the inhibitory mechanisms of a novel 49kDa FCRLA protein on
HLA class II-mediated T cell recognition of B-cell lymphomas. Studies are also planned to determine the
extent to which immune recognition can be restored by blocking FCRLA functions in vivo. Studies are also
planned to determine whether FCRLA blocking antibody augments immune recognition of B-cell lymphomas.
To accomplish the goals of the proposal, two specific aims are proposed: (Aim 1) To elucidate the molecular
mechanisms through which FCRLA disrupts HLA class II-peptide interactions and impairs T-cell recognition.
To accomplish this aim, we will test the hypothesis that B-cell lymphoma-derived 49kDa FCRLA protein
disrupts peptide binding to HLA class II and impairs CD4+ T cell recognition of tumors. (Aim 2) To investigate
the efficacy of FCRLA blockade in enhancing T cell recognition of B-cell lymphomas in vivo. To accomplish
this aim, we will test the hypothesis that B-cell lymphoma-shed 49kDa FCRLA may influence tumor growth in
vivo, and that blockade of FCRLA will augment antitumor immunit...

## Key facts

- **NIH application ID:** 10701531
- **Project number:** 1I01BX006101-01A1
- **Recipient organization:** RALPH H JOHNSON VA MEDICAL CENTER
- **Principal Investigator:** Azizul Haque
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2023-10-01 → 2027-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10701531

## Citation

> US National Institutes of Health, RePORTER application 10701531, A Novel Mechanism of Immune Escape by B-cell Lymphoma (1I01BX006101-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10701531. Licensed CC0.

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