# Investigating splicing-derived antigens in the context of Rbm10-mutant lung adenocarcinoma

> **NIH NIH F30** · HARVARD MEDICAL SCHOOL · 2024 · $53,974

## Abstract

Project summary:
The adaptive immune system can specifically recognize and kill cancer cells. Therapies that reinvigorate
tumor-specific CD8 T cells cure a subset of patients with lung cancer, prompting their FDA approval and use
as standard of care. Tumor-reactive T cells recognize cancer cell antigens -- displayed fragments of proteins
that are unique to tumor cells. To date, study of anti-tumor immunity has primarily focused on antigens derived
from somatic mutations in the cancer genome, which are insufficient to fully explain the anti-tumor immune
response. Moreover, mutation-derived neoantigens are generally unique to each tumor, and targeting them
might require bespoke treatments for each patient. The long-term goal of this proposal is to expand the
paradigm of cancer-specific antigens. Recent work has uncovered a novel class of cancer-restricted antigens
produced by abnormal splicing events. While several cancers harbor recurrent driver mutations in splicing
factors, few studies have explored the relationship between dysregulated splicing and tumor immunogenicity.
Notably, ~10% of lung adenocarcinomas feature loss-of-function mutations in RBM10, a critical splicing factor.
This work will examine splicing-derived antigens in Rbm10-deficient tumors. The central hypothesis is
that Rbm10 deficiency will generate aberrantly spliced transcripts, which will elicit an adaptive immune
response if translated and presented as novel antigens by tumor cells. This hypothesis will be tested in a well-
characterized murine model of lung adenocarcinoma by pursuing two specific aims. In Aim 1, mRNA
sequencing will be performed to characterize aberrant splicing events that occur in the context of Rbm10
deficiency. Mass spectrometry will be used to validate that aberrantly spliced RNAs produce antigens
presented to the immune systems. In Aim 2, CRISPR/Cas9 will be used to introduce Rbm10 mutations in an
immunocompetent, autochthonous murine model. Histologic and flow cytometric analyses will be performed on
infiltrating lymphocytes in Rbm10-deficient and proficient tumors to assess endogenous anti-tumor immunity.
This research study is innovative in that it proposes to empirically test the role of splicing-derived antigens in
anti-tumor immunity using genome engineering in autochthonous mouse models. It is significant because it
may identify new, tumor-restricted antigens that are targetable by cancer immunotherapies. While T-cell
targeted immunotherapies provide durable cures for patients with advanced cancer, prior studies emphasize a
limited set of cancer-specific T cell antigens. The ultimate objective of this work is to uncover novel
mechanisms to potentiate immune recognition of cancer cells, leading to the development of new therapies for
lung cancer.

## Key facts

- **NIH application ID:** 10839771
- **Project number:** 5F30CA278495-02
- **Recipient organization:** HARVARD MEDICAL SCHOOL
- **Principal Investigator:** Nicolas Mathey-Andrews
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $53,974
- **Award type:** 5
- **Project period:** 2023-09-01 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10839771

## Citation

> US National Institutes of Health, RePORTER application 10839771, Investigating splicing-derived antigens in the context of Rbm10-mutant lung adenocarcinoma (5F30CA278495-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10839771. Licensed CC0.

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