Hallmarks of response to immune checkpoint blockade

Abstract

Unprecedented advances have been made in the treatment of cancer through the use of immune checkpoint blockade, with approval of several checkpoint blockade regimens spanning multiple cancer types. However, responses to this form of therapy are not universal, and insights are clearly needed to identify optimal biomarkers of response and to combat mechanisms of therapeutic resistance. A working knowledge of the hallmarks of cancer yields insight into responses to immune checkpoint blockade, although the focus of this is rather tumour-centric and additional factors are pertinent, including host immunity and environmental influences. Herein, we describe the foundation for pillars and hallmarks of response to immune checkpoint blockade, with a discussion of their relevance to immune monitoring and mechanisms of resistance. Evolution of this understanding will ultimately help guide treatment strategies to enhance therapeutic responses.

Figure 1

The cellular immune response to cancer is complex and involves a diverse repertoire of immunoregulatory interactions principally involving antigen presenting cells (APC), T cells, and tumour cells. Presentation of distinct antigen epitopes to CD8⁺ and CD4⁺ T cells in the context of major histocompatibility complex class I (on APC or tumour cells directly) and class II (on APCs), respectively, facilitates tumour cell recognition, but numerous other molecular interactions (inset boxes) and input from paracrine and humoral factors (cytokines/chemokines, shown with arrowed lines) integrate to determine the ultimate outcome of immune recognition. Elaboration of survival and inflammatory cytokines, such as IL-2 and IFN-γ, can promote a cytotoxic (CD8⁺) T-cell response with consequent tumour-directed lytic activity mediated by release of cytotoxic granule contents (e.g., perforin and granyzme) as well as triggering of apoptotic pathways by tumouricidal cytokines (e.g., TNF-α and IFN-γ) and death receptor ligation (e.g., FAS:FAS-L). Debris released from apoptotic/necrotic tumour cells may be taken up by APC and presented in a cycle of immunogenic cell death. However, prolonged immune activation is adaptively opposed by upregulation of immunoinhibitory molecules (e.g., CTLA-4, PD-1, TIM3, TIGIT, and CTLA-4), or their ligands, many of which may be subverted by tumour cells in order to escape immune attack. Release of anti-inflammatory, immunoregulatory or Th2-skewed cytokines also contributes to dampening of the cellular response.

Figure 2

The core pillars and thematic hallmarks of anti-tumour immunity governing response to immune checkpoint blockade. Extensive research has identified numerous tumour-centric domains (shown in blue), including both static (existing genomic aberrations) and dynamic (epigenomic, metabolic and microenvironmental) features, which moderate anti-tumour immune responses and have impact on the efficacy of immune checkpoint blockade. Relevant metrics of overall immunocompetence, and systemic factors regulating the balance between immunotolerant and inflammatory states (e.g., innate and adaptive cell abundance and composition, immune cell circulation/sequestration, cytokine levels; shown in brown) are gradually being quantified. Environmental factors previously not implicated in directly modulating the anti-tumour response are now recognised to impact on immune checkpoint response (shown in green); principal among these sources of immunomodulation is the gut microbiota, while environmental stresses (e.g., thermal stress) and other tumour-remote immune-pathogen interactions may produce humoral factors that impact upon the specific anti-tumour response.