Combination anti–CTLA-4 plus anti–PD-1 checkpoint blockade utilizes cellular mechanisms partially distinct from monotherapies

Abstract

Immune checkpoint blockade therapy targets T cell-negative costimulatory molecules such as cytotoxic T lymphocyte antigen-4 (CTLA-4) and programmed cell death-1 (PD-1). Combination anti–CTLA-4 and anti–PD-1 blockade therapy has enhanced efficacy, but it remains unclear through what mechanisms such effects are mediated. A critical question is whether combination therapy targets and modulates the same T cell populations as monotherapies. Using a mass cytometry-based systems approach, we comprehensively profiled the response of T cell populations to monotherapy and combination anti–CTLA-4 plus anti–PD-1 therapy in syngeneic murine tumors and clinical samples. Most effects of monotherapies were additive in the context of combination therapy; however, multiple combination therapy-specific effects were observed. Highly phenotypically exhausted cluster of differentiation 8 (CD8) T cells expand in frequency following anti–PD-1 monotherapy but not combination therapy, while activated terminally differentiated effector CD8 T cells expand only following combination therapy. Combination therapy also led to further increased frequency of T helper type 1 (Th1)-like CD4 effector T cells even though anti–PD-1 monotherapy is not sufficient to do so. Mass cytometry analyses of peripheral blood from melanoma patients treated with immune checkpoint blockade therapies similarly revealed mostly additive effects on the frequencies of T cell subsets along with unique modulation of terminally differentiated effector CD8 T cells by combination ipilimumab plus nivolumab therapy. Together, these findings indicate that dual blockade of CTLA-4 and PD-1 therapy is sufficient to induce unique cellular responses compared with either monotherapy.

Determinants of Resistance to Checkpoint Inhibitors

“…Anti-PD-1 monotherapy results in the expansion of exhausted CD8+ T cells, while dual therapy results in the expansion of activated terminally differentiated effector CD8+ T cells [106]. Anti-CTLA-4 monotherapy increases the expansion of Th1-like CD4+ T cells, while dual therapy further increases the frequency of this population [106,107]. These data confirm that combinational therapies benefit from unique mechanisms of action that cannot be inferred from monotherapies alone.…”

“…Though both therapies target immune checkpoints that attenuate T-cell activation, they do so through distinct mechanisms that differentially affect specific T-cell populations [105]. Anti-PD-1 monotherapy results in the expansion of exhausted CD8+ T cells, while dual therapy results in the expansion of activated terminally differentiated effector CD8+ T cells [106]. Anti-CTLA-4 monotherapy increases the expansion of Th1-like CD4+ T cells, while dual therapy further increases the frequency of this population [106,107].…”

CD279 mediates the homeostasis and survival of regulatory T cells by enhancing T cell and macrophage interactions

“…CD279 antagonizes the TCR signaling pathway by a different mechanism compared to that of CD152 despite their synergy in the negative regulation of T cell activation [26]. Apart from differential expression pattern between CD279 and CD152 and their ligands in various cell subpopulations and tissues, they differ in their downstream signaling pathways with respect to inhibiting the upregulation of glucose metabolism and Akt phosphorylation mediated by CD3/CD28.…”

Simplified Admix Archaeal Glycolipid Adjuvanted Vaccine and Checkpoint Inhibitor Therapy Combination Enhances Protection from Murine Melanoma

“…While it has been reported that anti-PD-1 and anti-CTLA-4 combination therapy increases the incidence and severity of adverse effects, these were observed to be linked to the beneficial anti-tumor immune response; an inherently anti-"self" immune response capable of targeting non-tumor "self" targets throughout the body [50]. Management of immune-related adverse events (irAEs) are often handled with corticosteroids or discontinuation of treatment and are often considered by clinicians to be manageable with proper dosing.…”