# Project 2: Targeting Immune Vulnerabilities in Lung Cancer

> **NIH NIH P50** · UT SOUTHWESTERN MEDICAL CENTER · 2022 · $322,337

## Abstract

Project 2 Summary/Abstract
Immunotherapy with PD-1/PD-L1 checkpoint blockade (PCB) given alone or with chemotherapy now represents
the standard first-line treatment for NSCLC patients with wild-type (wt) EGFR and ALK. This is a major advance,
but the majority of NSCLC patients do not have an objective response to PCB. The molecular determinants of
PCB resistance are incompletely understood, although low tumor mutation burden and PD-L1 levels predict
some cases. Recently, we reported that LKB1 deficient (LD) tumors resulting from mutations or deletions in the
STK11/LKB1 gene are associated with an inert or “cold” immune phenotype and represent the largest
genomically-define subgroup with primary resistance to PCB, accounting for more than 30% of PCB resistance
in lung adenocarcinoma. The LKB1 protein is a master regulator of metabolism, energetic balance, and
nucleotide stores. Recent publications from our group and others indicate that LD tumors have a distinct
metabolic phenotype that includes enhanced lactate production, vulnerability to targeting intracellular nucleotide
pathways, and increased replicative stress (RS). These features may contribute to the “cold” immune phenotype.
The primary goals of Project 2 (P2) are to investigate new therapeutic approaches for targeting LD NSCLC and
enhancing antitumor immunity, with a focus on targeting the lactate pathway and RS. This focus integrates the
immunotherapy focus of Project 2 with studies in the other SPORE Projects and provides multiple Human
Endpoints for the SPORE Projects. We hypothesize that: 1) Enhanced lactate production or secretion
contributes to the “cold” immune phenotype in LD NSCLC; 2) LD NSCLC will be preferentially vulnerable to
targeting RS; and 3) targeting RS and/or lactate pathways may enhance antitumor immunity and response to
PCB. To test these hypotheses, in SA1 we will comprehensively characterize the immune phenotypes of LD
NSCLC using two sets of resected tumors: the MD Anderson ICON cohort and a validation cohort from UTSW
which have undergone metabolic labeling in P1. We will also examine immune cells in greater detail using single
cell RNA sequencing. In SA2 we will test whether targeting the lactate pathway using inhibitors of MCT4 and
LDHA can reverse LD-associated immunosuppression and enhance PCB efficacy. In SA3, we will target RS
using inhibitors of ATM, ATR, and the nucleoside analog 6-thio-dG in collaboration with P4, alone or in
combination with PCB. Significance: LD NSCLC tumors have a “cold” immune phenotype and frequent primary
resistance to PCB or PCB/chemotherapy. This patient population is larger than EGFR-mutant NSCLC and
comparably sized to metastatic pancreatic cancer. P2 aims to leverage our unique set of clinical and preclinical
resources to develop more effective therapeutic approaches for LD NSCLC patients, which can then translated
by our group and others into the clinic. P2 also provides the opportunity to spearhead a new paradigm of
genomic...

## Key facts

- **NIH application ID:** 10489261
- **Project number:** 5P50CA070907-23
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** John V. Heymach
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $322,337
- **Award type:** 5
- **Project period:** 1997-09-05 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10489261

## Citation

> US National Institutes of Health, RePORTER application 10489261, Project 2: Targeting Immune Vulnerabilities in Lung Cancer (5P50CA070907-23). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10489261. Licensed CC0.

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