mTOR pathway gene mutations predict response to immune checkpoint inhibitors in multiple cancers

Abstract

Background mTOR pathway is known to promote cancer malignancy and influence cancer immunity but is unknown for its role in immune checkpoint inhibitors (ICI) therapy. Methods Using Memorial Sloan-Kettering Cancer Center dataset (MSKCC), we extracted mTOR pathway gene mutations for stepwise Cox regression in 1661 cancer patients received ICI. We associated the mutation of the gene signature resulted from the stepwise Cox regression with the 1661 patients’ survival. Other 553 ICI-treated patients were collected from 6 cohorts for validation. We also performed this survival association in patients without ICI treatment from MSKCC as discovery (n = 2244) and The Cancer Genome Atlas (TCGA) as validation (n = 763). Pathway enrichment analysis were performed using transcriptome profiles from TCGA and IMvigor210 trial to investigate the potential mechanism. Results We identified 8 genes involved in mTOR pathway, including FGFR2, PIK3C3, FGFR4, FGFR1, FGF3, AKT1, mTOR, and RPTOR, resulted from stepwise Cox regression in discovery (n = 1661). In both discovery (n = 1661) and validation (n = 553), the mutation of the 8-gene signature was associated with better survival of the patients treated with ICI, which was independent of tumor mutation burden (TMB) and mainly attributed to the missense mutations. This survival association was not observed in patients without ICI therapy. Intriguingly, the mutation of the 8-gene signature was associated with increased TMB and PD1/PD-L1 expression. Immunologically, pathways involved in anti-tumor immune response were enriched in presence of this mutational signature in mTOR pathway, leading to increased infiltration of immune effector cells (e.g., CD8 + T cells, NK cells, and M1 macrophages), but decreased infiltration of immune inhibitory M2 macrophages. Conclusions These results suggested that mTOR pathway gene mutations were predictive of better survival upon ICI treatment in multiple cancers, likely by its association with enhanced anti-tumor immunity. Larger studies are warranted to validate our findings.

Phase 1 dose escalation study of FGFR4 inhibitor in combination with pembrolizumab in advanced solid tumors patients

“…36 The gene FGFR4 is involved in a distinct 8-gene mammalian target of rapamycin (mTOR) signature which is associated with increased PD-1/PD-L1 expression, and consequently, was predictive of better survival in patients upon immune checkpoint inhibitor (ICI) treatment in multiple cancers. 37 This is further supported by a preclinical trial that found lenvatinib plus an anti-PD-1 ICI activated immune pathways and could benefit ~20% of patients with HCC. 38 Results from the Phase 1b KEYNOTE-524 trial showed lenvatinib plus pembrolizumab had promising antitumor activity and manageable toxicities in patients with HCC.…”

“…By blocking FGFR4, lenvatinib has reduced tumor programmed death ligand 1 (PD‐L1) levels to improve anti‐PD‐1 efficacy 36 . The gene FGFR4 is involved in a distinct 8‐gene mammalian target of rapamycin (mTOR) signature which is associated with increased PD‐1/PD‐L1 expression, and consequently, was predictive of better survival in patients upon immune checkpoint inhibitor (ICI) treatment in multiple cancers 37 . This is further supported by a preclinical trial that found lenvatinib plus an anti‐PD‐1 ICI activated immune pathways and could benefit ~20% of patients with HCC 38 .…”

Malat1 Derepresses Mir-433-3p–mediated Rptor Suppression to Impair Autophagy and Drive Pyroptosis in Endotoxemia

“…In addition, because endotoxemia is also promoted by pyroptosis, which is characterized by the activation of inflammasomes and caspases as well as the creation of cell membrane pores (1,3), we validated the role of RPTOR in pyroptosis of LPS-treated HUVECs. RPTOR is one of the genes involved in mTOR pathways (34), and it has been found that dysregulation of mTOR activity is involved in pyroptotic cell death (35), suggesting that RPTOR can affect pyroptosis. As our experimental results revealed, the knockdown of RPTOR reduced levels of TNF-α, IL-1β, and IL-6, indicating that overexpressed RPTOR promoted inflammation.…”

Predictive value of 18F‐FDG PET/CT and serum tumor markers for tumor mutational burden in patients with non‐small cell lung cancer

“… 27 A previous study showed that carbohydrate metabolism had a positive correlation with TMB, 28 and another study showed that mutations of the mTOR pathway were associated with increased TMB. 29 Thus, the correlation between high MPs and high TMB may reflect increased glucose metabolism and activation of the mTOR pathway. Another alternative explanation for the correlation may be based on an innate immune response triggered by tumors with higher TMB.…”

“… 30 In the presence of the activated mTOR pathway, pathway enrichment was involved in antitumor immunity, enhanced antigen presentation, and increased infiltration of immune effector cells. 29 Moreover, tumor aggressiveness may be another intrinsic link between MPs and TMB. It is generally believed that tumors with high FDG uptake have a higher likelihood of aggressiveness, 31 and the phenotypic features related to aggressiveness may become more prominent as the genetic mutation rate increases.…”