Immune checkpoint blockade: a common denominator approach to cancer therapy

Abstract

The immune system recognizes and is poised to eliminate cancer but is held in check by inhibitory receptors and ligands. These immune checkpoint pathways, which normally maintain self-tolerance and limit collateral tissue damage during anti-microbial immune responses, can be co-opted by cancer to evade immune destruction. Drugs interrupting immune checkpoints, such as anti-CTLA-4, anti-PD-1, anti-PD-L1, and others in early development, can unleash anti-tumor immunity and mediate durable cancer regressions. The complex biology of immune checkpoint pathways still contains many mysteries, and the full activity spectrum of checkpoint-blocking drugs, used alone or in combination, is currently the subject of intense study.

Figure 1. Complex interactions between the CTLA-4/CD28 and PD-1 families of receptors and ligands

Shown are the defined interactions between the co-inhibitory (checkpoint) receptors, CTLA-4 and PD-1, and their ligands and related receptors. The two known ligands for CTLA-4 are CD80 (B7.1) and CD86 (B7.2). CD86 can “backwards signal” into antigen presenting cells (APCs) when engaged by CTLA-4, inducing the immune inhibitory enzyme indolamine 2’3’ dioxygenase (IDO). CD80 and CD86 also bind the co-stimulatory receptor CD28 on T cells. Recently, another B7 family member, ICOS-L, which was discovered as the ligand for the co-stimulatory receptor ICOS (not shown), was reported to bind to CD28 leading to co-stimulation independent of CD80 or CD86. The two defined ligands for PD-1, namely PD-L1 (B7-H1) and PD-L2 (B7-DC), bind to additional molecules. PD-L1 binds CD80 molecules expressed on activated T cells, mediating inhibition. Additionally, PD-L1 on APCs appears to provide inhibitory signals (“backwards signaling”) when it is engaged by PD-1. PD-L2 binds another molecule, repulsive guidance molecule b (RGMb), which is expressed on macrophages and some epithelial cell types and appears to deliver an inhibitory immune signal through an as yet undefined mechanism. Though not identified, genetic evidence from PD-1 knockout T cells and knockout mice suggests the existence of another receptor for PD-L2 that is co-stimulatory.

Figure 2. Two general mechanisms for expression of checkpoint ligands in the tumor microenvironment (TME)

The examples in this figure use the PD-1 ligand, PD-L1 for illustrative purposes although the concept likely applies to multiple checkpoint ligands. Top: Innate immune resistance. In some tumors, constitutive oncogenic signaling, such as through activation of the AKT pathway or gene amplification, can up-regulate PD-L1 expression on tumor cells independently of inflammatory signals in the TME. Bottom: Adaptive immune resistance refers to PD-L1 induction in tumors as an adaptation to sensing of immune attack. In adaptive resistance, PD-L1 is not constitutively expressed but rather, is induced by inflammatory signals such as IFN-g produced by T cells attempting to execute an active anti-tumor response. Expression of PD-L1 in a non-uniform distribution associated with lymphocyte infiltrates suggests adaptive induction in response to immune reactivity within the TME. Adaptive resistance can be generated by cytokine-induced PD-L1 expression on either tumor cells themselves or on leukocytes (macrophages, myeloid suppressor cells, dendritic cells or even lymphocytes) in the TME. Inhibition of tumor specific T cells by PD-L1- (or PD-L2)-expressing leukocytes may involve cross-presentation of tumor antigens such that PD-1-dependent inhibition is in cis. Adaptive resistance may be a common mechanism for the intratumoral expression of multiple immune checkpoint molecules.