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

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

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