IMMUNOLOGY2024™ Conference Recordings-Cell-intrinsic PD-L1 signals as actionable cancer immunotherapy targets

Video Transcription

Video Summary

The speaker described a new way to target PD-L1 in cancer beyond standard antibody-based immune checkpoint blockade. The key idea is that PD-L1 has important cell-intrinsic functions inside tumor cells, not just its well-known role on the cell surface binding PD-1. In multiple tumor models, PD-L1 promoted tumor growth, metastasis, DNA repair, and treatment resistance.<br /><br />A major focus was DNA damage response. Tumor PD-L1 was shown to support homologous recombination and to suppress CHEK2 ubiquitination, helping cancer cells survive DNA damage. Deleting PD-L1 or pharmacologically depleting it made tumors more sensitive to PARP inhibitors and CHEK1 inhibitors, even in immune-deficient mice, showing these effects are not dependent on PD-1 engagement or surface PD-L1 alone.<br /><br />The lab then screened FDA-approved or clinically usable drugs and found several that deplete tumor PD-L1, including cephapirin/ceftazidime-like antibiotics, chlorambucil, and telmisartan. These drugs could restore or enhance responses to immunotherapy and other cancer treatments. The talk also highlighted PD-L1 roles in the cell of origin of melanoma and in adipocytes, suggesting PD-L1 biology is broader than tumors alone.<br /><br />Overall, the message was that targeting intrinsic PD-L1 signals may overcome resistance and create new combination therapies.

Keywords

PD-L1

cancer

DNA damage response

homologous recombination

PARP inhibitors

CHEK2 ubiquitination

immunotherapy resistance