# ROLE OF THE HLA ANTIGEN PRESENTING MACHINERY (APM) IN RESISTANCE TO PD-1 AXIS BLOCKADE IN NON-SMALL CELL LUNG CANCER

> **NIH NIH R03** · YALE UNIVERSITY · 2020 · $83,795

## Abstract

Summary/Abstract:
In lung cancer, PD-1 blocking agents induce prominent and lasting clinical responses in nearly 20% of patients.
Increased clinical benefit is associated with elevated tumor PD-L1 protein; increased nonsynonymous
mutational load or HLA class-I restricted mutant neoantigens; and cognate CD8+ cytotoxic T cell presence.
However, the sensitivity and specificity of these factors to predict clinical benefit to therapy are limited. In most
cells, degrading cytosolic proteins including defective (e.g. mutant/truncated proteins) and viral peptides are
processed by the ubiquitin-proteasome pathway to generate relatively short 8-15 amino acid long peptides that
are presented by HLA class-I molecules to CD8+ T-cells in the plasma membrane. Recognition of these
peptides as non-self can trigger an adaptive immune response and activation of effector cytotoxic T-cells to
eliminate them. Adequate processing and presentation of peptides requires an intact antigen presenting
machinery (APM). Notably, downregulation and somatic mutations of APM components have been found with
variable frequency as immune evasion mechanism in diverse human tumors. Surprisingly, there is limited
information in lung cancer. In preliminary studies we found prominent association between mutations in APM
genes, HLA-I APM protein downregulation, reduced tumor inflammation and resistance to PD-1 axis blockade
in lung cancer. We hypothesize that HLA-I APM component defects occur in a proportion of human lung
cancers and mediate the anti-tumor immune evasion and resistance to anti-PD-1 therapy through blocking
antigen recognition.
We propose to evaluate the frequency and role of HLA-I APM defects in primary resistance to PD-1 axis
blockers in human lung cancer. We will systematically screen for altered protein levels of key HLA-I APM
components in samples from lung cancer patients from 2 large retrospective collections (Aim #1) and in cases
treated with PD-1 axis therapies at our institution (Aim #2). The protein levels of the HLA-I APM components
will be measured in situ using multiplexed quantitative immunofluorescence (QIF) panels. The HLA-I APM
components include i) immunoproteasome subunits LMP2, LMP7 and LMP10, ii) HLA-A, HLA-B and HLA-C
heavy chains, and ß2 microglobulin; iii) HLA class I-related peptide transporters TAP1 and TAP2; iv)
endoplasmic reticulum chaperones calnexin, calreticulin and tapasin; and v) MHC class I chain-related gene
MICA. We will also profile tumor-infiltrating lymphocytes (TILs) using QIF and study the association between
defective HLA-I APM components, tumor immune infiltration and sensitivity/response to PD-1 agents. The
results from these studies could reveal critical immune evasion pathways in lung cancer, develop predictive
biomarkers for optimal selection of patients for treatment with immune checkpoint blockers and suggest
possible therapeutic strategies for “non-inflamed” tumors.

## Key facts

- **NIH application ID:** 9878071
- **Project number:** 5R03CA219603-02
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** SOLDANO FERRONE
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $83,795
- **Award type:** 5
- **Project period:** 2019-03-01 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9878071

## Citation

> US National Institutes of Health, RePORTER application 9878071, ROLE OF THE HLA ANTIGEN PRESENTING MACHINERY (APM) IN RESISTANCE TO PD-1 AXIS BLOCKADE IN NON-SMALL CELL LUNG CANCER (5R03CA219603-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9878071. Licensed CC0.

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