# Interrogating the relationship between translational dynamics and non-canonical antigen presentation in lung cancer

> **NIH NIH R01** · H. LEE MOFFITT CANCER CTR & RES INST · 2024 · $485,494

## Abstract

ABSTRACT
Antigen presentation is a fundamental component of cancer immunity. The primary cytotoxic effectors of cancer
immunity are CD8+ T cells, which recognize peptide antigens presented in the context of Major Histocompatibility
Complex Class I (MHC-I). These foundational interactions between cancer cells and immune cells underlie the
success of immunotherapy. Antigens derived from somatic mutations, called “neoantigens”, have garnered
significant interest for the design of next generation immunotherapies. However, neoantigens suffer from
significant clonal heterogeneity within tumors and are specific to individual patients, limiting their widespread use
in engineered immunotherapies like cancer vaccines. To address this limitation, advances in mass spectrometry
have enabled direct measurement of the full repertoire of peptides known to bind MHC-I which is collectively
known as the “immunopeptidome”. Ever increasing depth and resolution in measuring the immunopeptidome
has revealed numerous sources of cancer specific antigens beyond neoantigens, including peptides derived
from cryptic translation events from novel unannotated open reading frames (nuORFs). Notably, immunotherapy
trials in cancer have revealed that antigen specific CD8+ T cell responses extend far beyond just mutated
neoantigens, especially in low tumor mutation burden patients, highlighting a critical need to understand
additional classes of tumor specific antigens like nuORFs. A deeper understanding of the mechanisms by which
nuORFs are presented may reveal novel pathways that could be pharmacologically targeted to increase cancer
immunogenicity. We hypothesize that nuORF antigens are synthesized, processed, and presented
through a non-canonical mechanism that utilizes cap-independent translation and co-translational
quality control to facilitate their presentation on MHC-I for immunosurveillance. Our preliminary analysis
demonstrates that specific translation inhibitors that promote cap-independent translation alter the antigenic
landscape of lung cancer. In this proposal, we will build upon these observations and utilize a combination of
sophisticated genetically engineered mouse models (GEMMs) and human cancer cell lines to define the
mechanisms that influence nuORF biosynthesis, processing, antigen presentation, and CD8+ T cell recognition.
In Aim 1, we will evaluate how pharmacological and physiological manipulation of translation alters presentation
and recognition of nuORF derived antigens. In Aim 2, we will assess the contribution of co-translational quality
control mechanisms in shaping non-canonical antigen presentation. Ultimately, the goal of this proposal is to
understand the mechanisms by which nuORFs are presented to more effectively engage this class of targets for
immunotherapy.

## Key facts

- **NIH application ID:** 10943035
- **Project number:** 1R01CA292692-01
- **Recipient organization:** H. LEE MOFFITT CANCER CTR & RES INST
- **Principal Investigator:** Alex Jaeger
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $485,494
- **Award type:** 1
- **Project period:** 2024-07-15 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10943035

## Citation

> US National Institutes of Health, RePORTER application 10943035, Interrogating the relationship between translational dynamics and non-canonical antigen presentation in lung cancer (1R01CA292692-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10943035. Licensed CC0.

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