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Treating ICB-resistant cancer by inhibiting PD-L1 via DHHC3 degradation induced by cell penetrating peptide-induced chimera conjugates

Shi, Yu-Ying, Fan, Gang, Tan, Ruirong, Li, Shan, Sun, Hua-Bing, Li, Rui, Yang, Mengni, Gao, Shanshan, Liu, Miao, Dai, Meng-Yuan·2024·Cell Death & Disease
DOI 10.1038/s41419-024-07073-yPMC PMC11442653

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Abstract

The current selection of ligands for both proteins of interest (POI) and E3 ubiquitin ligase significantly restricts the scope of targeted protein degradation (TPD) technologies. This study introduces cell-penetrating peptide-induced chimera conjugates (cp-PCCs) targeting the DHHC3 enzyme involved in PD-L1 palmitoylation. This approach disrupts PD-L1’s immunosuppressive function, enhancing anti-tumor immunity. We developed cp-PCCs to degrade DHHC3, directly linking DHHC3-mediated PD-L1 palmitoylation to PD-L1 stability on tumor cells. Our research utilized both in vitro assays and in vivo experiments in immune checkpoint blockade-resistant mouse models. We focused on a CRBN-based cp-PCC named PCC16, which demonstrated a DC50 of 102 nmol for DHHC3 degradation and significantly reduced PD-L1 levels. In resistant models, PCC16 not only robustly downregulated PD-L1 but also exhibited substantial anti-tumor activity in vivo without significant toxicity. This outperformed traditional inhibitors, showcasing the potential of cp-PCC technology to bypass current PROTAC limitations. Our findings suggest that cp-PCCs offer a promising method for targeting PD-L1 through DHHC3 inhibition and support their continued exploration as a versatile tool in cancer immunotherapy, especially for tumors resistant to standard treatments.

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Figures

Fig. 1 Preliminary effectiveness of cp-PCC compounds aimed at the palmitoylation and production of PD-L1. A The expression of ZDHHC3 protein in cancers based on the Human Protein Atlas: ZDHHC3 expression levels are evaluated according to the immunohistochemistry staining on cancer tissue samples of the Human Protein Atlas database. The X axis represents the cancer type. Pan-cancer includes 20 different cancer types. BRCA, breast cancer. CESC, cervical cancer. SKCM, skin cancer and melanoma. HNSC, head and neck cancer. The Y axis represents the percentage of patients with specific expression pattern of ZDHHC3. High, high expression. Low, low expression. None, no expression. B The correlation between PDL1 (CD274) and PD1(PDCD1), ZDHHC1, ZDHHC2, or ZDHHC3 expression in TCGA cancer types. TIMER2.0 Gene_Corr Module is used to evaluate the expression between two genes in different cancer types of TCGA database. The heatmap lists the purity-adjusted partial spearman’s rho (Cor) value as the degree of the correlation between two genes and the number (n) of patient cases in each cancer typer. C Western blot analysis was utilized to examine the expression of PD-L1 protein in MDA-MB-231 and C33A cells following the knockdown of DHHC1, DHHC2, and DHHC3. D A schematic representation of the structural design of cp-PCC. E Western blot analysis was conducted to assess the expression of PD-L1 protein in four cell lines (MDA-MB-231, C33A, FaDu, A375) following a 6-hour incubation with 10 µM PCC16/17/18, each corresponding to CRBN/VHL/IAP-based cp-PCC, respectively. Quantitative data are presented as mean ± standard error. Statistical analysis was performed using one-way ANOVA with Tukey’s post hoc test (n = 3): *P < 0.05, **P < 0.01, ***P < 0.001.
Fig. 1 Preliminary effectiveness of cp-PCC compounds aimed at the palmitoylation and production of PD-L1. A The expression of ZDHHC3 protein in cancers based on the Human Protein Atlas: ZDHHC3 expression levels are evaluated according to the immunohistochemistry staining on cancer tissue samples of the Human Protein Atlas database. The X axis represents the cancer type. Pan-cancer includes 20 different cancer types. BRCA, breast cancer. CESC, cervical cancer. SKCM, skin cancer and melanoma. HNSC, head and neck cancer. The Y axis represents the percentage of patients with specific expression pattern of ZDHHC3. High, high expression. Low, low expression. None, no expression. B The correlation between PDL1 (CD274) and PD1(PDCD1), ZDHHC1, ZDHHC2, or ZDHHC3 expression in TCGA cancer types. TIMER2.0 Gene_Corr Module is used to evaluate the expression between two genes in different cancer types of TCGA database. The heatmap lists the purity-adjusted partial spearman’s rho (Cor) value as the degree of the correlation between two genes and the number (n) of patient cases in each cancer typer. C Western blot analysis was utilized to examine the expression of PD-L1 protein in MDA-MB-231 and C33A cells following the knockdown of DHHC1, DHHC2, and DHHC3. D A schematic representation of the structural design of cp-PCC. E Western blot analysis was conducted to assess the expression of PD-L1 protein in four cell lines (MDA-MB-231, C33A, FaDu, A375) following a 6-hour incubation with 10 µM PCC16/17/18, each corresponding to CRBN/VHL/IAP-based cp-PCC, respectively. Quantitative data are presented as mean ± standard error. Statistical analysis was performed using one-way ANOVA with Tukey’s post hoc test (n = 3): *P < 0.05, **P < 0.01, ***P < 0.001.CC BY · PubMed Central
Fig. 2 The effect of cp-PCCs in reducing PD-L1 protein in vitro. A–C Western blot analysis was utilized to examine the expression of DHHC3/PD-L1 proteins in C33A cells following 6 h of treatment with varying concentrations of PCC16/17/18. D Comparative analysis of the DC50 values for PCC16/17/18. E–G Western blot analysis to assess the expression of DHHC3/PD-L1 proteins in C33A cells post-incubation with specific concentrations of PCC16/17/18 for different time periods. H Confocal microscopy was employed to observe the fluorescence intensity of PCC16/17/18 entering the cells at various time points. Quantitative data are presented as mean ± standard error. Statistical analysis was performed using one-way ANOVA with Tukey’s post hoc test (n = 3): *P < 0.05, **P < 0.01, ***P < 0.001.
Fig. 2 The effect of cp-PCCs in reducing PD-L1 protein in vitro. A–C Western blot analysis was utilized to examine the expression of DHHC3/PD-L1 proteins in C33A cells following 6 h of treatment with varying concentrations of PCC16/17/18. D Comparative analysis of the DC50 values for PCC16/17/18. E–G Western blot analysis to assess the expression of DHHC3/PD-L1 proteins in C33A cells post-incubation with specific concentrations of PCC16/17/18 for different time periods. H Confocal microscopy was employed to observe the fluorescence intensity of PCC16/17/18 entering the cells at various time points. Quantitative data are presented as mean ± standard error. Statistical analysis was performed using one-way ANOVA with Tukey’s post hoc test (n = 3): *P < 0.05, **P < 0.01, ***P < 0.001.CC BY · PubMed Central
Fig. 3 The synthesis and confirmation of the PCC-16. A Structure diagram of PCC16 (CRBN-based cp-PCC). B Synthetic Route of PCC16. C the area under the curve represents the sample’s absorbance at 220 nm during the HPLC procedure. D the parameters of each peak include RT: Retention Time. Height: The vertical measurement from the baseline to the peak. Area: The integrated area under each distinct peak. % Area: The proportion of the peak’s area relative to the total peak area. E Determination of Molecular Weight (MW): The MW calculation is based on the following equation: Actual MW = (Peak Value × Number of Charges) − Number of Positive Charges + Charge of the positive ion (Rhodamine B as the carrier). The calculated theoretical MW is 4729.3, in contrast to the experimentally observed MW of 4728.6.
Fig. 3 The synthesis and confirmation of the PCC-16. A Structure diagram of PCC16 (CRBN-based cp-PCC). B Synthetic Route of PCC16. C the area under the curve represents the sample’s absorbance at 220 nm during the HPLC procedure. D the parameters of each peak include RT: Retention Time. Height: The vertical measurement from the baseline to the peak. Area: The integrated area under each distinct peak. % Area: The proportion of the peak’s area relative to the total peak area. E Determination of Molecular Weight (MW): The MW calculation is based on the following equation: Actual MW = (Peak Value × Number of Charges) − Number of Positive Charges + Charge of the positive ion (Rhodamine B as the carrier). The calculated theoretical MW is 4729.3, in contrast to the experimentally observed MW of 4728.6.CC BY · PubMed Central
Fig. 4 PCC16 demonstrated stable binding affinity to the target protein DHHC3. A Confocal observation of DHHC3 binding with drug PCC16. Scale bar, 1 µM. B C33A cell lysates treated at different temperatures after incubation with 0.5 µM PCC16, with Western blot analysis of DHHC3 protein expression; C CETSA melting curve plotted. D Flow cytometry analysis of fluorescent cells after treatment with Rhodamine-labeled PCC16 at different concentration gradients; E C33A cells treated with PCC16 over time and concentration gradients, with cell toxicity of PCC16 measured by MTT assay.
Fig. 4 PCC16 demonstrated stable binding affinity to the target protein DHHC3. A Confocal observation of DHHC3 binding with drug PCC16. Scale bar, 1 µM. B C33A cell lysates treated at different temperatures after incubation with 0.5 µM PCC16, with Western blot analysis of DHHC3 protein expression; C CETSA melting curve plotted. D Flow cytometry analysis of fluorescent cells after treatment with Rhodamine-labeled PCC16 at different concentration gradients; E C33A cells treated with PCC16 over time and concentration gradients, with cell toxicity of PCC16 measured by MTT assay.CC BY · PubMed Central
Fig. 5 Examination of the degradation mechanism of cp-PCC compounds. A C33A cells pre-treated with/without MG132 for 4 h and then treated with PCC16/17/18, with Western blot analysis to detect PD-L1 protein levels; B Bar graph representing the quantification of grayscale values; C Confocal microscopy observation of the immunofluorescence intensity of PD-L1 protein under PCC16/17/18 ± MG132 conditions. Scale bar, 10 μM. Quantitative data expressed as mean ± standard error; analyzed by one-way ANOVA with Tukey’s post hoc test (n = 3): *P < 0.05, **P < 0.01, ***P < 0.001.
Fig. 5 Examination of the degradation mechanism of cp-PCC compounds. A C33A cells pre-treated with/without MG132 for 4 h and then treated with PCC16/17/18, with Western blot analysis to detect PD-L1 protein levels; B Bar graph representing the quantification of grayscale values; C Confocal microscopy observation of the immunofluorescence intensity of PD-L1 protein under PCC16/17/18 ± MG132 conditions. Scale bar, 10 μM. Quantitative data expressed as mean ± standard error; analyzed by one-way ANOVA with Tukey’s post hoc test (n = 3): *P < 0.05, **P < 0.01, ***P < 0.001.CC BY · PubMed Central
Fig. 6 Reduction of PD-L1 through DHHC3 degradation by cp-PCCs increased the sensitivity to chemotherapy and bolstered anti-tumor immunity. A Western blot analysis of the effects of PCC series drugs and PD-L1 monoclonal antibody on PD-L1 protein levels in C33A cells; B TUNEL assay to assess apoptosis in cervical cancer cells treated with cisplatin and PCC16; C Ki67 assay for evaluating the proliferation of cervical cancer cells treated with cisplatin and PCC16; D Plate cloning experiment analyzing the proliferation of cervical cancer cells treated with cisplatin and PCC16; E In a C33A-T cell co-culture model, ELISA was used to measure IFN-γ and TNF-α expression levels after treatment with different concentrations of PCC16; F Hoechest33528 staining in the co-culture system to observe apoptosis of C33A cells after treatment with different concentrations of PCC16. Quantitative data are expressed as mean ± standard error; analyzed by one-way ANOVA with Tukey’s post hoc test (n = 3): *P < 0.05, **P < 0.01, ***P < 0.001.
Fig. 6 Reduction of PD-L1 through DHHC3 degradation by cp-PCCs increased the sensitivity to chemotherapy and bolstered anti-tumor immunity. A Western blot analysis of the effects of PCC series drugs and PD-L1 monoclonal antibody on PD-L1 protein levels in C33A cells; B TUNEL assay to assess apoptosis in cervical cancer cells treated with cisplatin and PCC16; C Ki67 assay for evaluating the proliferation of cervical cancer cells treated with cisplatin and PCC16; D Plate cloning experiment analyzing the proliferation of cervical cancer cells treated with cisplatin and PCC16; E In a C33A-T cell co-culture model, ELISA was used to measure IFN-γ and TNF-α expression levels after treatment with different concentrations of PCC16; F Hoechest33528 staining in the co-culture system to observe apoptosis of C33A cells after treatment with different concentrations of PCC16. Quantitative data are expressed as mean ± standard error; analyzed by one-way ANOVA with Tukey’s post hoc test (n = 3): *P < 0.05, **P < 0.01, ***P < 0.001.CC BY · PubMed Central
Fig. 7 PCC16 showed effective therapeutic results both in vitro and in vivo in treating ICB-resistant tumors. A Schematic of treatment regimens in mice with PD-L1 monoclonal antibody, BMS-8, and PCC series drugs; B Images of mouse tumors on Day 14 post-treatment; C Tumor growth curves for different treatments (n = 4); D Body weight change curves for mice under different treatments; E Comparison of tumor weights in different treatment groups (n = 4); F Representative tumor sections collected post-treatment (n = 4) stained with TUNEL (green) for apoptotic cells, G Ki67 (pink) for proliferating cells, and DAPI (blue) for nuclei. H Western blot analysis of PD-L1 expression in tumor tissues from each group; I H&E and IHC analysis of PD-L1 protein expression post-PCC16 treatment; J H&E images of heart, liver, spleen, lung, and kidney tissues from mice in each group; scale bar, 50 μm. Quantitative data expressed as mean ± standard error; analyzed by one-way ANOVA with Tukey’s post hoc test (n = 3): *P < 0.05, **P < 0.01, ***P < 0.001.
Fig. 7 PCC16 showed effective therapeutic results both in vitro and in vivo in treating ICB-resistant tumors. A Schematic of treatment regimens in mice with PD-L1 monoclonal antibody, BMS-8, and PCC series drugs; B Images of mouse tumors on Day 14 post-treatment; C Tumor growth curves for different treatments (n = 4); D Body weight change curves for mice under different treatments; E Comparison of tumor weights in different treatment groups (n = 4); F Representative tumor sections collected post-treatment (n = 4) stained with TUNEL (green) for apoptotic cells, G Ki67 (pink) for proliferating cells, and DAPI (blue) for nuclei. H Western blot analysis of PD-L1 expression in tumor tissues from each group; I H&E and IHC analysis of PD-L1 protein expression post-PCC16 treatment; J H&E images of heart, liver, spleen, lung, and kidney tissues from mice in each group; scale bar, 50 μm. Quantitative data expressed as mean ± standard error; analyzed by one-way ANOVA with Tukey’s post hoc test (n = 3): *P < 0.05, **P < 0.01, ***P < 0.001.CC BY · PubMed Central

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Authors
Shi, Y.-Y., Fan, G., Tan, R., Li, S., Sun, H.-B., Li, R., Yang, M., Gao, S., Liu, M., & Dai, M.-Y.
Venue
Cell Death & Disease
Publisher
Springer Science and Business Media LLC
Published
2024-09-30
Volume
15
Issue
9
ISSN
2041-4889
DOI
10.1038/s41419-024-07073-y
PMC
PMC11442653
Cited by
28
References
4
Language
en
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correction (2024-11-18)
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