Comprehensive genomic profiling of triple-negative breast cancer metastases identifies role of PKD1 in immunotherapy resistance
Xiu-Zhi Zhu, Yi-Fan Zhou, Xiao-Han Ying, Yun-Yi Wang, Xiao-Hong Ding, Kun-Yu Zhang, Zhi-Ming Shao, Xi Jin, Yi-Zhou Jiang, Zhong-Hua Wang
Xiu-Zhi Zhu, Yi-Fan Zhou, Xiao-Han Ying, Yun-Yi Wang, Xiao-Hong Ding, Kun-Yu Zhang, Zhi-Ming Shao, Xi Jin, Yi-Zhou Jiang, Zhong-Hua Wang
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Research Article Genetics Oncology

Comprehensive genomic profiling of triple-negative breast cancer metastases identifies role of PKD1 in immunotherapy resistance

Abstract

The multi-omics data represented by genomic data from patients with metastatic triple-negative breast cancer (TNBC) is crucial for precision treatment, yet data on genomic alterations in metastatic cohorts and Chinese populations remains limited. We performed targeted sequencing of 296 metastatic TNBC samples from 296 patients treated at Fudan University Shanghai Cancer Center (October 2018 to November 2020) using a 484-gene panel, identifying 796 metastatic events across 18 organ sites. We characterized the genomic landscape of TNBC metastases and identified marked enrichment of polycystin-1 (PKD1) mutations in metastatic lesions — a finding validated in an independent paired primary metastasis cohort (n = 105). Notably, PKD1 mutations were associated with resistance to anti–PD-1 therapy, as validated across 3 clinical trials (NCT03805399, NCT04129996, and NCT04395989). Multi-omics analyses, combined with functional in vitro and in vivo mechanistic studies, revealed that PKD1 modulated the “desert” tumor immune microenvironment via C-C motif chemokine ligand 2 (CCL2), and targeting CCL2 could reverse immunotherapy resistance. This comprehensive genomic characterization of metastases enhances our understanding of tumor evolution, identifies PKD1 as a previously uncharacterized regulator of immune evasion to our knowledge, and suggests a potential therapeutic strategy to overcome immunotherapy resistance.

Authors

Xiu-Zhi Zhu, Yi-Fan Zhou, Xiao-Han Ying, Yun-Yi Wang, Xiao-Hong Ding, Kun-Yu Zhang, Zhi-Ming Shao, Xi Jin, Yi-Zhou Jiang, Zhong-Hua Wang

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Figure 5

PKD1 expression facilitates tumor immune evasion.

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PKD1 expression facilitates tumor immune evasion. (A and B) PKD1 knockdo...
(A and B) PKD1 knockdown efficiency in 4T07 cells was validated by Western blotting (A; polycystin-1 protein) and qRT-PCR (B; PKD1 mRNA). (C) Growth curves of 4T07 cells in the PKD1-KD and NC groups. (D and E) Transwell migration (D) and clonogenic assays (E) of 4T07 cells in the PKD1-KD and NC groups. Representative images (left) and quantitation (right) are shown. Scale bar: 200 μm. (F and G) PKD1 overexpression efficiency in 67NR cells, analyzed by Western blotting (F) and qRT-PCR (G). (H) Growth curves of 67NR cells in the PKD1-OE and NC groups. (I and J) Transwell migration (I) and clonogenic assays (J) of 67NR cells in the PKD1-OE and NC groups. Representative images (left) and quantitation (right) are shown. Scale bar: 200 μm. (K) Schematic of the TNBC orthotopic tumor model and lung metastasis model construction. (L and M) Tumor growth in 4T07 (L) and 67NR (M) orthotopic allografts established in immunodeficient mice. (N and O) Tumor growth curves of the 4T07 (N) and 67NR (O) orthotopic tumor models in immunocompetent mice. (P) Number of lung metastases in immunocompetent mice bearing 4T07 tumors. (Q) Number of lung metastases in immunocompetent mice bearing 67NR tumors. Dunnett’s test was used in B–E, L, N and P. Two-tailed unpaired Student’s t test was used in G–J, M, O and Q. NC, negative control; KD, knockdown; OE, overexpression; TNBC, triple-negative breast cancer. *P < 0.05; **P < 0.01; ***P < 0.001.