Table 5 Summary of key findings related to drug resistance mechanisms induced by tumor microenvironments using single-cell sequencing

AML

Paired scRNA-seq and TCR repertoire profiling

TCR repertoires of CD8 + T cells expanded in responders or patients with stable disease after PD-1 blockade treatment and contracted in therapy-resistant patients. GZMK expression and stem-cell feature were observed in the T-cells of responders. Chr7/7q loss was a marker for resistance to PD-1 blockade therapy.

Noted the importance of TCR repertoires. TCR repertories were changed during therapy and indicated treatment response. Chr7/7q was identified as a prognostic indicator for PD-1 blockade therapy in AML.

[38]

AML

scRNA-seq, scDNA-seq, bulk TCRβ sequencing

Combined therapy of anti-PD-1 (pembrolizumab) and hypomethylating agent (decitabine) was feasible and had the best response of stable diseases or better in 6 of 10 patients. Clonal expansion of CD8 + effector memory T cells with PD-1 expression was associated with immune-related adverse events.

Proposed that adding pembrolizumab to current decitabine therapy was clinically feasible in patients with relapsed AML.

[114]

CML

scRNA-seq;

Dasatinib induced the terminal differentiation and exhaustion of CD8 + T cells and NK cells, where the addition of IFN-α reversed this process and increased the number of unique putative epitope-specific TCR clusters.

Supported that the combination of IFN-α with TKI therapy will improve the therapeutic outcome.

[115]

AML

scRNA-seq; CITE-seq; ChIP-seq; ATAC-seq

A novel immunoregulatory effect by histone deacetylase inhibition (HDACi) was associated with the IFN-α pathway. Plasmacytoid dendritic cells (pDC) produce IFN-α after HDACi treatment with increased H3K27 acetylation at the IFN gene. Depletion of pDCs impaired the therapeutic efficiency of HDACi.

Noted that the epigenetic activation of pDCs by HDACi enhances antitumor immunity, suggesting further invention of immunotherapies for epigenetic modulation in pDCs.

[116]

T-ALL

scRNA-seq

T-ALL patient–derived tumor xenografts (PDXs) models were developed. Screened out 39 drugs from 433 clinical-stage molecules using the PDXs model. Discovered that endothelial cells (ECs) and T-ALL cells interact reciprocally, mitigating drug responses in T-ALL PDXs.

Ultimately discovered 5 effective drugs from the drug screening and tested in vivo with therapeutic effects. First developed a T-ALL/EC platform that can help elucidate the leukemia-microenvironment interactions with endothelial cells.

[117]