Reprogramming NK cells and macrophages via combined antibody and cytokine therapy primes tumors for elimination by checkpoint blockade.

Chensu Wang,Heikyung Suh,Ang Cui,Simon Liang,Yash Agarwal,Darrell J Irvine,Stefani Spranger,Maurice Bukenya,Ayush Thomas,Aereas Aung,Parastoo Amlashi,Nir Hacohen,Dikshant Pradhan,Charles A Whittaker

doi:10.1016/j.celrep.2021.110021

Abstract

SUMMARYTreatments aiming to augment immune checkpoint blockade (ICB) in cancer often focus on T cell immunity, but innate immune cells may have important roles to play. Here, we demonstrate a single-dose combination treatment (termed AIP) using a pan-tumor-targeting antibody surrogate, half-life-extended interleukin-2 (IL-2), and anti-programmed cell death 1 (PD-1), which primes tumors to respond to subsequent ICB and promotes rejection of large established tumors in mice. Natural killer (NK) cells and macrophages activated by AIP treatment underwent transcriptional reprogramming; rapidly killed cancer cells; governed the recruitment of cross-presenting dendritic cells (DCs) and other leukocytes; and induced normalization of the tumor vasculature, facilitating further immune infiltration. Thus, innate cell-activating therapies can initiate critical steps leading to a self-sustaining cycle of T cell priming driven by ICB.

Highlights

Immune checkpoint blockade (ICB) therapies based on the administration of antibodies against the T cell inhibitory molecules cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and programmed cell death 1 (PD-1, or its ligands) have been approved for the treatment of a variety of malignancies alone or in combination (Antonia et al, 2017; Hellmann et al, 2018; Hodi et al, 2010; Reck et al, 2016; Socinski et al, 2018)
We identified a potent four-component immunotherapy comprised of an anti-tumor antibody (‘‘A’’), half-lifeextended interleukin-2 (‘‘I’’), anti-PD-1 (‘‘P’’), and a peptide vaccine (‘‘V,’’ with the combination treatment abbreviated as AIPV hereafter), which cured a majority of animals in several difficultto-treat transplanted and genetically engineered mouse models (GEMMs) of cancer (Moynihan et al, 2016)
CD4+ and CD8+ T cells, Natural killer (NK) cells, conventional type 1 dendritic cells and cDC2s, NK cells, and neutrophils were all recruited to the tumor over the course of 6 days following a single dose of AIPV, and the CD8/Treg ratio shifted dramatically (Figures S1B and S1C)

Summary

Introduction

Immune checkpoint blockade (ICB) therapies based on the administration of antibodies against the T cell inhibitory molecules cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and programmed cell death 1 (PD-1, or its ligands) have been approved for the treatment of a variety of malignancies alone or in combination (Antonia et al, 2017; Hellmann et al, 2018; Hodi et al, 2010; Reck et al, 2016; Socinski et al, 2018). One factor associated with outcome is the number of infiltrating T cells prior to or during early treatment (Chen et al, 2016; Tumeh et al, 2014), introducing the notion of ‘‘hot’’ (inflamed and highly infiltrated) and ‘‘cold’’ (immunosuppressive and non-infiltrated) tumors (Galon et al, 2006) Those patients responding to ICB most often exhibit a ‘‘hot’’ tumor phenotype. We identified a potent four-component immunotherapy comprised of an anti-tumor antibody (‘‘A’’), half-lifeextended interleukin-2 (‘‘I’’), anti-PD-1 (‘‘P’’), and a peptide vaccine (‘‘V,’’ with the combination treatment abbreviated as AIPV hereafter), which cured a majority of animals in several difficultto-treat transplanted and genetically engineered mouse models (GEMMs) of cancer (Moynihan et al, 2016) This treatment was dependent on CD8+ T cells and

Results

Discussion

Conclusion