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Several first-line anti-hypertensives act on fibrosarcoma progression and PD1ab blockade therapy
Jianwen Sun1, Chaoxiong Zhang2, Xinhao Su2
1Department of Orthopaedics, The First Affiliated Hospital of Jishou University, The People's Hospital of Xiangxi Autonomous Prefecture, Jishou, China.
Purpose:
Patients are typically diagnosed with both hypertension and fibrosarcoma. Medical oncologists must prescribe suitable anti-hypertensive medications while considering anti-tumor drugs. Recently, immunotherapy has become prominent in cancer treatment. Nonetheless, it is unknown what role anti-hypertensive medications will play in immunotherapy.
Methods:
We examined the effects of six first-line anti-hypertensive medications on programmed cell death protein 1 antibody (PD1ab) in tumor treatment using a mouse model of subcutaneous fibrosarcoma. The drugs examined were verapamil, losartan, furosemide, spironolactone, captopril, and hydrochlorothiazide (HCTZ). The infiltration of CD8+ T cells was examined by immunohistochemistry. Additionally, several in vitro and in vivo assays were used to study the effects of HCTZ on human fibrosarcoma cancer cells to explore its mechanism.
Results:
Verapamil suppressed tumor growth and showed an improved effect on the tumor inhibition of PD1ab. Captopril did not affect tumor growth but brought an unexpected benefit to PD1ab treatment. In contrast, spironolactone and furosemide showed no effect on tumor growth but had an offset effect on the PD1ab therapy. Consequently, the survival time of mice was also significantly reduced. Notably, losartan and HCTZ, especially HCTZ, promoted tumor growth and weakened the effect of PD1ab treatment. Consistent results were observed in vivo and in vitro using the human fibrosarcoma cell line HT1080. We determined that the Solute Carrier Family 12 Member 3 (SLC12A3), a known target of HCTZ, may be the principal factor underlying its effect-enhancing properties through mechanism studies employing The Cancer Genome Atlas (TCGA) data and in vivo and in vitro assays.
Conclusion:
Verapamil and captopril potentiated the anti-tumor effect of PD1ab, whereas spironolactone and furosemide weakened the effect of PD1ab on tumor inhibition. Alarmingly, losartan and HCTZ promoted tumor growth and impaired the effect of PD1ab. Furthermore, we preliminarily found that HCTZ may promote tumor progression through SLC12A3. Based on this study, futher mechanism researches and clinical trials should be conducted in the future.
Insights
Certain blood pressure medications impact cancer immunotherapy. Losartan and hydrochlorothiazide (HCTZ) worsened immunotherapy outcomes in fibrosarcoma models, while verapamil and captopril improved them.
Area of Science:
- Oncology
- Pharmacology
- Immunotherapy
Background:
- Hypertension and fibrosarcoma often coexist, requiring careful medication selection.
- Immunotherapy is a growing cancer treatment modality.
- The interaction between antihypertensive drugs and immunotherapy is not well understood.
Purpose of the Study:
- To investigate the effects of common antihypertensive medications on programmed cell death protein 1 antibody (PD1ab) immunotherapy in a fibrosarcoma mouse model.
- To explore the underlying mechanisms of observed drug effects, particularly for hydrochlorothiazide (HCTZ).
Main Methods:
- A mouse model of subcutaneous fibrosarcoma was used to test six first-line antihypertensive drugs: verapamil, losartan, furosemide, spironolactone, captopril, and HCTZ.
- Immunohistochemistry was employed to assess CD8+ T cell infiltration.
- In vitro and in vivo assays were conducted to elucidate the mechanism of HCTZ action on human fibrosarcoma cells (HT1080).
Main Results:
- Verapamil and captopril enhanced the anti-tumor efficacy of PD1ab therapy.
- Spironolactone and furosemide showed no impact on tumor growth but diminished PD1ab efficacy.
- Losartan and HCTZ promoted tumor growth and weakened PD1ab treatment effects, with HCTZ's mechanism potentially involving Solute Carrier Family 12 Member 3 (SLC12A3).
Conclusions:
- Antihypertensive medications have differential effects on PD1ab immunotherapy efficacy in fibrosarcoma.
- Verapamil and captopril show potential as adjuncts to PD1ab therapy.
- Losartan and HCTZ may be detrimental when used concurrently with PD1ab immunotherapy, warranting further investigation into HCTZ's role via SLC12A3.
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