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CDK4/6 inhibitors and the pRB-E2F1 axis suppress PVR and PD-L1 expression in triple-negative breast cancer

Mariusz Shrestha1,2, Dong-Yu Wang3, Yaacov Ben-David4,5

  • 1Department of Laboratory Medicine & Pathobiology, University of Toronto, Toronto, Ontario, Canada. m.shrestha@mail.utoronto.ca.

Oncogenesis
|May 25, 2023
PubMed

Insights

Retinoblastoma tumor suppressor loss and E2F1 activation increase immune checkpoint modulators like PD-L1 in triple-negative breast cancer. CDK4/6 inhibitors reduce PD-L1, but acids can counteract this effect.

Area of Science:

  • Oncology
  • Immunology
  • Molecular Biology

Background:

  • Immune-checkpoint (IC) modulators, such as poliovirus receptor (PVR) and programmed death ligand 1 (PD-L1), are crucial in regulating immune responses and represent therapeutic targets in cancers like triple-negative breast cancer (TNBC).
  • The retinoblastoma tumor suppressor (pRB) is a key regulator of cell growth via E2F transcription factors, and its inactivation is linked to cancer metastasis, but its role in IC modulator expression remains unclear.

Purpose of the Study:

  • To investigate the relationship between pRB/E2F pathway and the expression of immune checkpoint modulators (PVR, PD-L1) in TNBC.
  • To elucidate the impact of CDK4/6 inhibition and other factors on PD-L1 regulation.

Main Methods:

  • Analysis of RB-loss and E2F1/E2F2 signatures in relation to PVR and PD-L1 expression.
  • Experimental manipulation of pRB, E2F1, and CDK4/6 activity in TNBC cells.
  • Assessment of palbociclib, hydrochloric acid, and lactic acid effects on PVR and PD-L1 levels.

Main Results:

  • RB-loss and high E2F1/E2F2 signatures positively correlate with PVR and PD-L1 expression in TNBC.
  • pRB represses PVR and PD-L1, while RB depletion and E2F1 induce their expression.
  • The CDK4/6 inhibitor palbociclib decreases PVR and PD-L1, partly by affecting SPOP-mediated degradation.
  • Hydrochloric acid and lactic acid, a glycolysis byproduct, both induce PD-L1 and PVR expression, counteracting palbociclib's effects.

Conclusions:

  • The CDK4/6-pRB-E2F pathway integrates cell proliferation control with the regulation of immune checkpoint modulators.
  • This pathway influences PD-L1 turnover through both transcriptional promotion (via pRB-E2F1) and degradation (via SPOP).
  • Findings have significant implications for understanding cancer progression and optimizing anti-CDK4/6 and IC therapies, highlighting the impact of solubilizing agents and metabolic byproducts.

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