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MEK inhibition overcomes chemoimmunotherapy resistance by inducing CXCL10 in cancer cells [LLC1]

ABSTRACT: Chemotherapy with anti PD-1/PD-L1 mAb has become the standard of care for patients with metastatic non-small cell lung cancer (NSCLC). Using lung tumor models, where pemetrexed-platinum chemotherapy (PEM/CDDP) remains unable to synergize with immune checkpoint inhibitors (ICI), we linked failure of this treatment with its inability to induce CXCL10 expression and CD8+ T cell recruitment. Using drug screening, we showed that combining a MEK inhibitor (MEKi) with PEM/CDDP triggers CXCL10 secretion by cancer cells and CD8+ T cell recruitment, and restores ICI efficacy. PEM/CDDP plus MEKi promotes optineurin (OPTN)-dependent mitophagy, resulting in CXCL10 production in a mitochondrial DNA and TLR9-dependent manner. TLR9 or autophagy/mitophagy processes genetic inactivation of abort the antitumor efficacy of PEM/CDDP plus MEKi/anti PD-L1 therapy. In human NSCLC, high OPTN, TLR9 and CXCL10 expression is associated with better response to ICI. Our results underline the role of TLR9 and OPTN-dependent mitophagy in enhancing chemoimmunotherapy efficacy.

ORGANISM(S): Mus musculus

PROVIDER: GSE190264 | GEO | 2021/12/08

REPOSITORIES: GEO

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Project description:Immune checkpoint inhibitors (ICIs), antibodies targeting PD-1/PD-L1 or CTLA4 have revolutionized cancer management but are associated with devastating immune-related adverse events (irAEs) including myocarditis. The main risk factor for ICI myocarditis is the use of combination PD-1 and CTLA4 inhibition. ICI-myocarditis is often fulminant and is pathophysiologically characterized by myocardial infiltration of T lymphocytes and macrophages. While much has been learned regarding the role of T-cells in ICI-myocarditis, little is understood regarding the identity, transcriptional diversity, and functions of infiltrating macrophages. We employed an established murine ICI myocarditis model (Ctla4+/-Pdcd1-/- mice) to explore the cardiac immune landscape using single-cell RNA-sequencing, immunostaining, and molecular imaging. We observed marked increases in CCR2+ monocyte-derived macrophages and CD8+ T-cells in this model. The macrophage compartment was heterogeneous and displayed marked enrichment in an inflammatory CCR2+ subpopulation expressing Cxcl9, Cxcl10, Gbp2b, and Fcgr4 that originated from CCR2+ monocytes. Importantly, a similar macrophage population expressing CXCL9, CXCL10, and CD16α (human homologue of mouse FcgR4) were found selectively in patients with ICI myocarditis compared to other forms of heart failure and myocarditis. In silico prediction of cell-cell communication suggested interactions between T-cells and Cxcl9+Cxcl10+ macrophages via IFN-γ and CXCR3 signaling pathways. Depleting CD8+T-cells and blockade of IFN-γ signaling blunted the emergence of Cxcl9+Cxcl10+ macrophages in the heart and attenuated myocarditis suggesting that this interaction was necessary for disease pathogenesis. Collectively, these data demonstrate that ICI-myocarditis is associated with the emergence of a specific population of inflammatory macrophages and suggest the possibility that IFN-γ blockade may serve as an effective treatment for this devastating condition.

Project description:Transcriptome analysis was used to identify gene expression changes during development of sunitinib resistance in a renal cell carcinoma patient-derived xenograft (PDX) model. During the response phase, tumors exhibited a 91% reduction in volume, characterized by induction of TNFRSF1A, TNFAIP3, NFKB2, CCL2, CCL20, BIRC3, and MOAP1. Ingenuity Pathway Analysis indicated decreased expression of cell survival genes during tumor response to sunitinib. In this model, after 4 weeks of treatment, tumors developed resistance despite continued administration of the tyrosine kinase inhibitor (TKI) sunitinib (40 mg/kg/d p.o.). Resistance was associated with increased expression of VEGFA, EPO, IL-8, ANGPT2, TNFRSF12, MAPK3/7, MAPKBP1, and increased cell survival genes, suggesting activation of angiogenesis and MAPK/ERK pathways. Tumor lysate mRNA evaluated for murine gene expression to examine the contribution of host effects, indicated that tumor response was associated with downregulation of immune cell trafficking, cellular movement, and inflammatory response genes. During tumor escape, genes associated with cellular movement, inflammatory response, and immune cell trafficking were strongly induced, along with intratumoral accumulation of myeloid derived suppressor cells (MDSC), indicating a role for host factors during emergence of sunitinib resistance. The same PDX model was used to assess anti-tumor efficacy of sunitinib combined with MEK inhibitor (MEKi) PD-0325901 (4 mg/kg/d p.o.) using different schedules. The most effective treatment regimen was either continuous treatment with both drugs or switching from sunitinib to PD-0325901 monotherapy at d30, which reduced tumor volume by 78.6% (p=0.0241) and 88.5% (p=0.0068), respectively. The combination of MEKi with TKI (sunitinib, axitinib, or pazopanib) suppressed levels of phospho-MEK1/2 and phospho-ERK1/2, and decreased intratumoral MDSC. Thus, continuous treatment with sunitinib alone did not maintain tumor response, and addition of a MEKi abrogated resistance leading to prolonged survival. Study was comprised of three experimental groups (pre-treatment, response, escape). All tumors came from the same PDX model. There were four biological replicates in each group. Four mice were used, with each of the 3 groups per mouse. There were no control or reference samples.

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MEK inhibition overcomes chemoimmunotherapy resistance by inducing CXCL10 in cancer cells [LLC1]

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