pts had bone metastases. Response to chemotherapy was: 4 SD, and 1 PD. Three of 7 corresponding CNV profiles were evaluable for HRD score analysis with 100% positive. Conclusion: Pathogenic BRCA1/2 mutations occur in 1.7% of advanced NSCLC with 71% of somatic mutations suggesting its value for exploring new therapeutic strategies in this population
BackgroundKRAS-mutant non-small cell lung cancers (NSCLC) have exhibited unique response patterns to immunotherapy based on their co-occurring mutations. Patients harboring KRAS & STK11/LKB1 co-mutations (KL) have experienced shorter progression-free and overall survival compared to those with only KRAS mutations (K). Despite their limited responses, KL tumors exhibit a tumor mutational burden comparable to their K counterparts, suggesting the presence of additional mechanisms impairing antigen-specific responses. Accordingly, here we investigated the role of the MHC I antigen processing and presentation pathway in KL tumors.MethodsTCGA lung adenocarcinoma (LUAD) data were investigated for changes in expression of HLA molecules and chaperones involved in antigen processing and presentation. In mice, we performed single cell RNA sequencing of resected LKR13 K and KL tumors to evaluate changes in the tumor microenvironment and intrinsic differences in tumor antigen processing machinery. In vitro experiments were performed using the ovalbumin antigen to evaluate changes in antigen-specific T cell responses.ResultsExpression of HLA-A (p<0.0001), -B (p<0.0001), -C (p<0.0001), and beta2-microglobulin (B2M, p<0.0002) was downregulated in KL tumors from TCGA, as were expression of the TAP1 (p<0.001) and TAP2 (p<0.001) transporter associated with antigen processing subunits. LKR13 KL tumors exhibited similar patterns with lower H2-k1 (p<0.0001), H2-d1 (p<0.0001), B2m (p<0.0001), Tap1 (p<0.0001) and Tap2 (p<0.0001). As a result, LKR13 KL were resistant to recognition (p<0.005) and killing (56.9% K versus 7.8% KL) by OT-I T cells. Decreased expression of IFN-gamma-regulated genes such as PSMB8 (p<0.001), PSMB9 (p<0.0001), PSMB10 (p<001), CIITA (p<0.0001), NLRC5 (p<0.0001), IFNGR1 (p<0.0001), and IFNGR2 (p<0.0001) was also noted in KL tumors. Accordingly, KL tumors were unresponsive to exogenous IFN-gamma stimulation, maintaining repression of surface H2-Kb and resistance to T cell recognition (p<0.05) and killing (12.8% K versus 4% KL). Expression of T cell chemokines and receptors CXCR3 (p<0.0001), CXCL9 (p<0.0001), and CXCL10 (p<0.0001) was also repressed, potentially contributing to the lack of T cell infiltration in KL tumors.ConclusionsKRAS-mutant tumors harboring STK11/LKB1 alterations have an immunosuppressed phenotype and resistance to PD-1/PD-L1 inhibitors. Our findings provide evidence that these alterations are associated with markedly reduced antigen presentation and resistance to T cell killing, responsiveness to IFN-gamma stimulation, and impaired production of T cell chemokines, providing mechanistic insights into this immunosuppressed phenotype that could help guide the development of new therapeutic strategies for enhancing anti-tumor immunity.
Deletion or loss of function mutations of the STK11/LKB1 tumor suppressor are associated with primary resistance to immunotherapy in KRAS-mutant lung adenocarcinoma (LUAD) and drive metabolic reprogramming of tumor cells. We observed that LKB1-deficient tumors were resistant to anti-angiogenic therapy in the hypoxic and nutrient-depleted or acidic tumor microenvironment (TME). We determined that MYC which is elevated in LKB1-deficient cells, regulated the expression of the lactate transporter, MCT4. Moreover, knockdown of MYC decreases glycolysis and cell proliferation. Therefore, we hypothesize that metabolic changes in LKB1-deficient tumor cells is at least partially driven by MYC upregulation, and that depletion of MYC or targeting of key enzymes or transporters downstream of MYC such as MCT4 may abrogate lactate reutilization and sensitize LKB1-deficient tumors to anti-angiogenic therapy. To explore the impact of MYC on lactate metabolism in LKB1-deficient NSCLC cells, we performed isotope tracing in KRAS mutant (K) and KRAS mutant LKB1 knockout (KL) syngeneic murine lung cancer cells. 13C3-lactate tracing revealed that isotopologues were significantly enriched in TCA components such as pyruvate, citrate and a-ketoglutarate in KL cells. Meanwhile, lactate-treated KL cells shows less reactive oxygen species (ROS), suggesting that LKB1-deficient tumor cells reutilize lactate as an energy source more efficiently than LKB1-intact cells. MCT4 KO significantly abrogated lactate incorporation into TCA cycle. Similarly, MYC knockdown or MCT4 KO decreased lactate-induced oxygen consumption, but increased ROS levels. In contrast, exhausted T cells were inefficient at lactate reutilization, and high levels of lactate increased ROS in T cells. Hence, LKB1-deficient tumors have a survival advantage over T cells in the lactate-rich TME. We queried scRNAseq data from K, KL and KL MCT4KO syngeneic models and similarly observed that KL tumor cells exhibited elevated hypoxia and angiogenesis gene expression signatures, which was reversed by MCT4 KO. However, ROS detoxification was decreased in T cells from KL tumors but increased in MCT4 KO tumors. Finally, we injected KL murine tumor cells into immunocompetent mice, and randomly treated them with vehicle or the VEGF blocking antibody, DC101. MYC knockdown or MCT4 KO sensitized KL tumors to VEGF inhibition, and significantly increased overall survival. Collectively, our data indicates that in LKB1-deficient tumors, upregulation of MYC promotes tumor cell metabolic reprogramming and that targeting MYC or MCT4 can inhibit lactate reutilization and enhance the efficacy of anti-angiogenic agents. These findings provide insight into the mechanisms driving the aggressive phenotype of KRAS-mutant LKB1-deficient tumors and identify a novel therapeutic strategy for targeting this patient population. Citation Format: Yu Qian, David Molkentine, Chendong Yang, Ana Galan Cobo, Irene Guijarro, Minghao Dang, Alissa Poteete, Peixin Jiang, Ferdinandos Skoulidis, Linghua Wang, Alexandre Reuben, John D. Minna, Ralph J. DeBerardinis, John V. Heymach. MYC mediates enhanced lactate reutilization and resistance to anti-angiogenesis therapy in preclinical models of LKB1-deficient NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 271.
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