# Rebalancing protein homeostasis enhances tumor antigen presentation

> **NIH NIH F31** · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · 2022 · $23,322

## Abstract

PROJECT SUMMARY / ABSTRACT
 Cancers arise through a combination of genetic and epigenetic changes that facilitate their
immortality, but simultaneously create foreign antigens, which should render neoplastic cells detectable
by the immune system and target them for destruction. Despite the remarkable success of
immunotherapies targeting endogenous effector T-cells, many cancers still evade immune recognition.
A critical component of successful immunotherapy is robust antigen presentation through Major
Histocompatibility Complex Class I (MHC-I) [10, 15, 34]. Since antigens can be derived from the mutant
proteome present in cancers, it would be expected that tumor types with high mutational load, such as
lung adenocarcinoma (LUAD), are characterized by strong T cell responses. However, many patients
with these tumor types either fail to respond to immunotherapy, or relapse after initial treatment.
Inherent to malignant transformation is the induction of proteotoxic stress due to the accumulation
of mutated, conformationally aberrant proteins [5]. To overcome these stresses, cancer cells are
exquisitely dependent on molecular chaperones [28]. This phenomenon suggests that immunogenicity
generated by antigens derived from the aberrant genome and epigenome in cancer is dampened by the
function of chaperones and the protein folding machinery. Thus, I hypothesize that inducers of protein
misfolding stress lead to increased antigen presentation by MHC-I molecules and increased
immunogenicity.
I propose to explore the impact of destabilizing the mutant proteome of LUAD in order
to reveal it to the host’s immune system. The aims are as follows:
Aim 1: Analyze the impact of protein misfolding stress on antigen presentation by MHC-I
molecules. In this aim I will interrogate the impact of subtoxic doses of small molecule modulators of
protein folding on antigen presentation in human and murine LUAD cell lines. We expect to expose the
mutant proteome to the immune system without disrupting protein folding machineries essential
functions. Additionally, I will genetically and pharmacologically perturb the pathways involved in antigen
presentation, in order to understand the mechanisms by which modulators of proteotoxic stress amplify
and diversify antigen presentation in LUAD cell lines.
Aim 2: Analyze the role of HSP90i and other inducers of proteotoxic stress in a hyper-mutational
mouse model of lung adenocarcinoma (LUAD)
Low-dose treatment with modulators of cytoplasmic proteotoxic stress will be tested for their ability to
stimulate an anti-tumor response in a hyper-mutational mouse model of LUAD.
This proposal will highlight mechanistically novel strategies to drive anti-tumor immune responses.

## Key facts

- **NIH application ID:** 10478021
- **Project number:** 5F31CA239493-04
- **Recipient organization:** MASSACHUSETTS INSTITUTE OF TECHNOLOGY
- **Principal Investigator:** Grissel Cervantes Jaramillo
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $23,322
- **Award type:** 5
- **Project period:** 2019-09-11 → 2022-11-20

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10478021

## Citation

> US National Institutes of Health, RePORTER application 10478021, Rebalancing protein homeostasis enhances tumor antigen presentation (5F31CA239493-04). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10478021. Licensed CC0.

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