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Drug-tolerant persisters and immunotherapy persister cells exhibit cross-resistance and share common survival mechanisms

Cell Death & Differentiation (2025)Cite this article

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Abstract

Persisters are a rare sub-population of tumor cells that survive anti-cancer therapy and are thought to be a major cause of recurrence. These cells have been identified following both drug- and immune-therapy but are generally considered to be distinct entities. Since both pharmacological agents and immune cells often kill via apoptosis, we tested a hypothesis that both types of cells survive based on reduced mitochondrial apoptotic sensitivity, which in turn would yield a similar and reciprocal multi-agent resistant phenotype. Supporting this hypothesis, we indeed observed that IPCs acquired a reduced sensitivity to multiple drug classes and radiotherapy, suggesting non-immune mechanisms are important in the survival of cancer cells after immunotherapy. Likewise, DTPs developed not only a reduced sensitivity to multiple drug classes and radiotherapy, but also acquired a reduced sensitivity to T cell killing. Both IPCs and DTPs developed decreased sensitivity to mitochondrial apoptosis. A sub-population of IPCs downregulated antigen and upregulated PD-L1. Intriguingly, in the IPCs that didn’t employ these mechanisms of resistance, a greater decrease in sensitivity to mitochondrial apoptosis was observed, suggesting that the presence or absence of a resistance mechanism can exert selective pressures over the emergence of others. Targeting anti-apoptotic dependencies in persisters increased sensitivity to chemotherapy or CAR T therapy. These results suggest that common biological mechanisms underly survival of persisters, whether derived from immune or drug therapy, and offer an explanation for the acquired cross-resistance to these two types of therapies often observed in the clinic.

Highlights

  • Immunotherapy persister cells (IPCs) are less sensitive to drugs and radiation.

  • Drug tolerant persisters (DTPs) are less sensitive to radiation and CAR T cell attack.

  • IPCs and DTPs are less sensitive to mitochondrial apoptosis.

  • Targeting anti-apoptotic dependencies helps eliminate IPCs/DTPs.

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Fig. 1: IPCs are less sensitive to chemotherapies and radiotherapy.
Fig. 2: DTPs are less sensitive to chemotherapies, radiotherapy and T cell attack.
Fig. 3: Immunotherapy persister cells acquired a reduction in sensitivity to mitochondrial apoptotic cell death.
Fig. 4: A greater reduction in sensitivity to mitochondrial apoptotic cell death was observed in the immunotherapy persister cells that did not downregulate antigen or upregulate PD-L1.
Fig. 5: Drug-tolerant persister cells acquire an altered apoptotic priming signature.
Fig. 6: IPCs possess therapeutically targetable anti-apoptotic dependencies.
Fig. 7: Targeting mitochondrial anti-apoptotic dependencies in IPCs using BH3 mimetics increases their sensitivity to EGFR-CAR T cell attack and drug treatment.
Fig. 8: DTPs possess targetable anti-apoptotic dependencies that can be therapeutically harnessed to decrease DTP survival and increase sensitivity to pharmacological agents.
Fig. 9: RNA sequencing revealed that pro-inflammatory and KRAS signaling hallmark pathways were upregulated in both IPCs and DTPs.

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Acknowledgements

This work utilized an Illumina NovaSeq X Plus that was purchased with funding from a National Institutes of Health SIG grant 1S10OD036228-01.

Funding

This work was funded by NCI R01 249062 (AL and MVM). AL also receives funding from Blood Cancer United’s Discovery Grant Program.

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Authors and Affiliations

  1. Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA

    Maria Davern, Cole J. Turner, Daryl Griffin, Lara Bencsics, Brenda C. Chan, Jasmine Yun-Tong Kung, Michael L. Olson, Cheyanne Walker Williams, Shaili Soni, Leah Krotee, Michael Yorsz, Gabriella Antonellis, Patrick H. Lizotte, Cloud P. Paweletz, Jeremy Ryan, David Barbie, Patrick Bhola & Anthony Letai

  2. Cancer Center, Harvard, Boston, MA, USA

    Filippo Birocchi, Antonio Josue Almazan & Marcela V. Maus

  3. Harvard T. H. Chan School of Public Health, Boston, MA, USA

    Kristopher A. Sarosiek

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  1. Maria Davern
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Contributions

All authors contributed to this study. MD and AL designed the study and wrote the manuscript. MD, CJT, DG, LB, BCC, JY-TK, MLO, CWW, SS, LK, MY, GA, FB and AJA performed experiments. JR, PB, KAS, and MVM provided advice on experimental design. DB, CPP, and PHL provided cell lines.

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Correspondence to Anthony Letai.

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Davern, M., Turner, C.J., Griffin, D. et al. Drug-tolerant persisters and immunotherapy persister cells exhibit cross-resistance and share common survival mechanisms. Cell Death Differ (2025). https://doi.org/10.1038/s41418-025-01656-8

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