Of immune checkpoint maladies and remedies: The throwing of jabs in the oncogenic ring of PDAC

Abstract

The upregulation of co-inhibitory checkpoint receptors/ligands that inactivate antitumor T-cells, the enhancement of Tregs-mediated trogocytosis that contribute delayed maturation of antigen presenting cell (APC), and the high Tregs/CD⁺8 ratio that maintained low threshold of CD⁺8 cells in the tumor microenvironment (TME); all represent the nuances in the immune evasive strategies of pancreatic ductal adenocarcinoma (PDAC). PDAC is the most aggressive type of pancreatic cancers characterized by poor prognosis and extremely low survivability. Over the years, fraternity of scientists have developed therapeutic agents that can bolster the capacity of the antitumor immunity, usually via the inhibition of immune checkpoints. While this immune checkpoint inhibition therapy represents one major jab from immunity to PDAC, this cancer remains highly resistant due to the acme of desmoplasia in its TME. In this review, we discuss the mechanisms of various checkpoint receptors/ligands axes that are relevant to the fitness of PDAC in its oncogenic ring. These checkpoints include PD-1, CTLA-4, ICOS, TIM-3, TIGIT, BTLA, BTN3A, and VISTA. In addition, we provided evidences that are relevant to the understanding of immune checkpoint inhibition, with extensive outline of immune checkpoint inhibitors that are critical to the treatment of PDAC. Finally, we discuss recently known intricacies of PDAC-mediated immunosuppression, and current advances in treatment options. Having realized that the overall scenario between PDAC and antitumor immunity is like the throwing of jabs in a ring, we therefore discuss future directions and prospect that can knock out PDAC in favor of immunity and humanity.

Keywords: Immune checkpoint inhibitors; Immune therapy; Immunosuppression; PDAC; Tumor microenvironment.