Targeting ubiquitin protein ligase E3 component N-recognin 5 in cancer cells induces a CD8+ T cell mediated immune response.

UBR5 is a nuclear phosphoprotein of obscure functions. Clinical analyses reveal that amplifications and overexpression occur in over 20% cases of human breast cancers. Breast cancer patients carrying genetic lesions with overexpression have significantly reduced survival. Experimental work and demonstrates that UBR5, functioning as an oncoprotein, plays a profound role in breast cancer growth and metastasis. UBR5 drives tumor growth largely through paracrine interactions with the immune system, particularly through inhibiting the cytotoxic response mediated by CD8 T lymphocytes, whereas it facilitates metastasis in a tumor cell-autonomous manner via its transcriptional control of key regulators of the epithelial-mesenchymal transition, ID1 and ID3. Furthermore, simultaneous targeting of UBR5 and PD-L1 yields strong therapeutic benefit to tumor-bearing hosts. This work significantly expands our scarce understanding of the pathophysiology and immunobiology of a fundamentally important molecule and has strong implications for the development of novel immunotherapy to treat highly aggressive breast cancers that resist conventional treatment.