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Small-molecule PIK-93 modulates the tumor microenvironment to improve immune checkpoint blockade response.

ABSTRACT: Immune checkpoint inhibitors (ICIs) targeting PD-L1 immunotherapy are state-of-the-art treatments for advanced non-small cell lung cancer (NSCLC). However, the treatment response of certain patients with NSCLC is unsatisfactory because of an unfavorable tumor microenvironment (TME) and poor permeability of antibody-based ICIs. In this study, we aimed to discover small-molecule drugs that can modulate the TME to enhance ICI treatment efficacy in NSCLC in vitro and in vivo. We identified a PD-L1 protein-modulating small molecule, PIK-93, using a cell-based global protein stability (GPS) screening system. PIK-93 mediated PD-L1 ubiquitination by enhancing the PD-L1-Cullin-4A interaction. PIK-93 reduced PD-L1 levels on M1 macrophages and enhanced M1 antitumor cytotoxicity. Combined PIK-93 and anti-PD-L1 antibody treatment enhanced T cell activation, inhibited tumor growth, and increased tumor-infiltrating lymphocyte (TIL) recruitment in syngeneic and human peripheral blood mononuclear cell (PBMC) line-derived xenograft mouse models. PIK-93 facilitates a treatment-favorable TME when combined with anti-PD-L1 antibodies, thereby enhancing PD-1/PD-L1 blockade cancer immunotherapy.

SUBMITTER: Lin CY

PROVIDER: S-EPMC10081850 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature

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Small-molecule PIK-93 modulates the tumor microenvironment to improve immune checkpoint blockade response.

Lin Chia-Yi CY Huang Kuo-Yen KY Kao Shih-Han SH Lin Ming-Shiu MS Lin Chih-Chien CC Yang Shuenn-Chen SC Chung Wei-Chia WC Chang Ya-Hsuan YH Chein Rong-Jie RJ Yang Pan-Chyr PC

Science advances 20230407 14

Immune checkpoint inhibitors (ICIs) targeting PD-L1 immunotherapy are state-of-the-art treatments for advanced non-small cell lung cancer (NSCLC). However, the treatment response of certain patients with NSCLC is unsatisfactory because of an unfavorable tumor microenvironment (TME) and poor permeability of antibody-based ICIs. In this study, we aimed to discover small-molecule drugs that can modulate the TME to enhance ICI treatment efficacy in NSCLC in vitro and in vivo. We identified a PD-L1 p ...[more]

PMID: 37027467

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Project description:Small cell lung cancer (SCLC) has recently been subcategorized into neuroendocrine (NE)-high and NE-low subtypes showing 'immune desert' and 'immune oasis' phenotypes, respectively. Here, we aimed to characterize the tumor microenvironment according to immune checkpoints and NE subtypes in human SCLC tissue samples at the protein level. In this cross-sectional study, we included 32 primary tumors and matched lymph node (LN) metastases of resected early-stage, histologically confirmed SCLC patients, which were previously clustered into NE subtypes using NE-associated key RNA genes. Immunohistochemistry (IHC) was performed on formalin-fixed paraffin-embedded TMAs with antibodies against CD45, CD3, CD8, MHCII, TIM3, immune checkpoint poliovirus receptor (PVR), and indoleamine 2,3-dioxygenase (IDO). The stroma was significantly more infiltrated by immune cells both in primary tumors and in LN metastases compared to tumor nests. Immune cell (CD45+ cell) density was significantly higher in tumor nests (P = 0.019), with increased CD8+ effector T-cell infiltration (P = 0.003) in NE-low vs NE-high tumors. The expression of IDO was confirmed on stromal and endothelial cells and was positively correlated with higher immune cell density both in primary tumors and in LN metastases, regardless of the NE pattern. Expression of IDO and PVR in tumor nests was significantly higher in NE-low primary tumors (vs NE-high, P < 0.05). We also found significantly higher MHC II expression by malignant cells in NE-low (vs NE-high, P = 0.004) tumors. TIM3 expression was significantly increased in NE-low (vs NE-high, P < 0.05) tumors and in LN metastases (vs primary tumors, P < 0.05). To our knowledge, this is the first human study that demonstrates in situ that NE-low SCLCs are associated with increased immune cell infiltration compared to NE-high tumors. PVR, IDO, MHCII, and TIM3 are emerging checkpoints in SCLC, with increased expression in the NE-low subtype, providing key insight for further prospective studies on potential biomarkers and targets for SCLC immunotherapies.

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Small-molecule PIK-93 modulates the tumor microenvironment to improve immune checkpoint blockade response.

Publications

Small-molecule PIK-93 modulates the tumor microenvironment to improve immune checkpoint blockade response.

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