Distinct Cellular Mechanisms Underlie Anti-CTLA-4 and Anti-PD-1 Checkpoint Blockade

Abstract

Summary Immune checkpoint blockade is able to achieve durable responses in a subset of patients, however we lack a satisfying comprehension of the underlying mechanisms of anti-CTLA-4 and anti-PD-1 induced tumor rejection. To address these issues we utilized mass cytometry to comprehensively profile the effects of checkpoint blockade on tumor immune infiltrates in human melanoma and murine tumor models. These analyses reveal a spectrum of tumor infiltrating T cell populations that are highly similar between tumor models and indicate that checkpoint blockade targets only specific subsets of tumor infiltrating T cell populations. Anti-PD-1 predominantly induces the expansion of specific tumor infiltrating exhausted-like CD8 T cell subsets. In contrast, anti-CTLA-4 induces the expansion of an ICOS+ Th1-like CD4 effector population in addition to engaging specific subsets of exhausted-like CD8 T cells. Thus, our findings indicate that anti-CTLA-4 and anti-PD-1 checkpoint blockade induced immune responses are driven by distinct cellular mechanisms.

Combination of dual mTORC1/2 inhibition and immune-checkpoint blockade potentiates anti-tumour immunity

“…3A), supporting recent observations that immune checkpoint blocking antibodies preferentially expand exhausted phenotype T-cells in both mice and man. 22 However, T-cell populations appeared functionally less exhausted in vistusertib treated tumour bearing mice, exhibiting lower expression of the exhaustion marker PD-1 (Fig. 3A-C).…”

“…3). 22 In contrast, through pleiotropic effects to modulate Th1 promoting innate immune cytokines, and selectively enhance effector CD8 + T-cell viability, vistusertib was able to confer a less suppressive tumour microenvironment (Fig. 3).…”

Contrasting impact of corticosteroids on anti-PD-1 immunotherapy efficacy for tumor histologies located within or outside the central nervous system

“…38 Hence, the mechanism of action of anti-PD-1 therapy is to reverse the exhaustion of pre-existing tumor-residing T cells, thus improving their effector functions to carry out tumor regressions. 39–41 Depending on the context and their sensitivity, if tumor-infiltrating T cells undergo adequate exposure to corticosteroids, then the benefits conferred by anti-PD-1 therapy may be diminished or completely lost. Endogenous and exogenous corticosteroids have been demonstrated to reduce antitumor immunity and counteract cancer immunotherapy in a murine autochthonous pancreatic ductal carcinoma model.…”

A B cell-derived gene expression signature associates with an immunologically active tumor microenvironment and response to immune checkpoint blockade therapy

“…1 Several studies have shown that anti-PD-1/PD-L1 and anti-CTLA-4 act through distinct mechanisms. 2,3 CTLA-4 interferes in the early stages of T cell activation by inhibiting stimulatory signaling that is required following antigen-T cell receptor (TCR) binding. Conversely, PD-1 is involved later in T cell activation and acts by attenuating TCR signaling following engagement with its ligands, PD-L1 or PD-L2.…”