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 genomically-guided, tailored immunotherapy for PCB-resistant tumors.
Although PD-1/PD-L1 immune checkpoint blockade (PCB) therapy has transformed the treatment of non-small cell lung cancer (NSCLC) patients, the majority still do not have an objective response to PCB and the molecular determinants of therapeutic resistance are not well understood. We have found that STK11/LKB1 mutant NSCLC is one the largest genomic subgroups associated with a ?cold? immune phenotype, accounting for ~40% of the primary resistance to checkpoint blockade therapy, and we hypothesize that there are distinct biological features of these tumors that may contribute their immunologically inert phenotype and that represent therapeutic vulnerabilities. In this proposal will leverage unique preclinical and clinical resources to comprehensively investigate the immune landscape of STK11/LKB1 mutant lung adenocarcinoma and test whether targeting two potential therapeutic vulnerabilities- lactate metabolism and replication stress- can enhance antitumor immunity in these tumors.
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