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Intermittent MEK inhibition with GITR co-stimulation rescues T cell function for increased efficacy with CTLA-4 blockade in solid tumor models

ABSTRACT: MEK inhibitors (MEKis) have limited success with MAPK/ERK pathway dependent cancers due to various resistance mechanisms tumor cells can employ. CH5126766 (CKI27) is a novel inhibitor that binds to MEK and prevents release of RAF, reducing the relief of negative feedback commonly observed with other MEKis. We observed that CKI27 increased MHC expression on tumor cells and improved T cell mediated killing. Yet, CKI27 also decreased T cell proliferation, activation, and cytolytic activity by inhibiting the MAPK/ERK pathway that is activated downstream of T cell receptor signaling. Therefore, we aimed to balance the positive and negative immunomodulatory effects of MEKis for optimal combination with immunotherapy. Intermittent administration of CKI27 allowed T cells to partially recover and co-stimulation via GITR and OX-40 agonist antibodies completely alleviated inhibition of function. In Kras mutant lung and colon tumor mouse models, intermittent CKI27 and anti-GITR significantly decreased tumor growth and prolonged survival when further combined with CTLA-4 immune checkpoint blockade. Moreover, this triple combination increased CD8+ and CD4+ T cell proliferation, activation, and effector/memory subsets in the tumor draining lymph nodes and tumors and led to intra-tumoral Treg destabilization. These data, collectively, will allow for more informed decisions when optimizing combination regimens by overcoming resistance, reducing toxicity, and generating long-term immune responses.

ORGANISM(S): Mus musculus

PROVIDER: GSE264426 | GEO | 2024/06/12

REPOSITORIES: GEO

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Project description:Carcinogenesis is a multistep process in which cells accumulate multiple genetic alterations, as they progress to a more malignant phenotype. It has been proposed that sequential accumulation of gene abnormalities in specific genes drives the transition from non-tumorous epithelia through preneoplastic lesion/benign tumor to cancer. Histologically, progression to invasive oral squamous cell carcinoma (OSCC) follows multistep ordered series beginning with mucosal epithelial cell hyperplasia, followed by dysplasia, carcinoma in situ and invasive carcinoma. It is therefore speculated that genetic alterations-mediated multistep carcinogenesis would be involved in OSCC development, but their detailed molecular mechanisms are unknown. Herein, we clarified the comprehensive gene expression patterns and carried out an enrichment analysis using DNA microarray data obtained from an OSCC pathological specimen, which consists of non-tumor region, carcinoma in situ lesion and invasive carcinoma lesion. Numerous numbers of gene expression and signal activation were altered in the OSCC development. Of them, the expression of p63 was increased and MEK/ERK-MAPK pathway was activated in carcinoma in situ lesion as well as in invasive carcinoma lesion. Immunohistochemical analyses revealed that p63 was initially upregulated in carcinoma in situ lesions and ERK was sequentially activated in invasive carcinoma lesions in OSCC specimens. ADP-ribosylation factor (ARF)-like 4c (ARL4C), the expression of which is reportedly induced by p63 and/or MEK/ERK-MAPK pathway in OSCC cells, has been shown to promote tumorigenesis. Immunohistochemically, in OSCC specimens, ARL4C was more frequently detected in tumor lesions, especially in invasive carcinoma lesions than in carcinoma in situ lesions. Additionally, ARL4C and phosphorylated ERK were merged at high frequency in invasive carcinoma lesions. Loss-of-function experiments using inhibitors and siRNAs revealed that p63 and EGFR-MEK/ERK-MAPK cooperatively induce ARL4C expression in OSCC cells. These results suggest that the stepwise activation of p63 and EGFR-MEK/ERK-MAPK contributes to OSCC tumor cell growth though regulation of ARL4C expression.

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Intermittent MEK inhibition with GITR co-stimulation rescues T cell function for increased efficacy with CTLA-4 blockade in solid tumor models

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