Combination of CD40 Agonism and CSF-1R Blockade Reconditions Tumor-Associated Macrophages and Drives Potent Antitumor Immunity.

Karla R Wiehagen,Michael Quigley,Andressa A Smith,Iqbal S Grewal,Natasha M Girgis,Douglas H Yamada,Raluca I Verona,Szeman Ruby Chan

doi:10.1158/2326-6066.cir-17-0258

Abstract

Efficacious antitumor immune responses must overcome multiple suppressive mechanisms in the tumor microenvironment to control cancer progression. In this study, we demonstrate that dual targeting of suppressive myeloid populations by inhibiting CSF-1/CSF-1R signaling and activation of antigen-presenting cells with agonist anti-CD40 treatment confers superior antitumor efficacy and increased survival compared with monotherapy treatment in preclinical tumor models. Concurrent CSF-1R blockade and CD40 agonism lead to profound changes in the composition of immune infiltrates, causing an overall decrease in immunosuppressive cells and a shift toward a more inflammatory milieu. Anti-CD40/anti-CSF-1R-treated tumors contain decreased tumor-associated macrophages and Foxp3+ regulatory T cells. This combination approach increases maturation and differentiation of proinflammatory macrophages and dendritic cells and also drives potent priming of effector T cells in draining lymph nodes. As a result, tumor-infiltrating effector T cells exhibit improved responses to tumor antigen rechallenge. These studies show that combining therapeutic approaches may simultaneously remove inhibitory immune populations and sustain endogenous antitumor immune responses to successfully impair cancer progression. Cancer Immunol Res; 5(12); 1109-21. ©2017 AACR.

Highlights

To escape detection by the immune system, tumors foster an immunosuppressive environment and produce signals that subdue antitumor immune responses [1]
To determine which myeloid subsets depend on the CSF-1/CSF1R axis, CSF-1R expression was assessed in distinct populations of myeloid cells in established, untreated CT26 tumors
The highest frequencies of CSF-1Rhi cells were detected in Ly6Glo Ly6Cint MHC IIhi and Ly6Clo Tumor-associated macrophages (TAMs), with no significant differences in CSF-1R expression between MHC IIhi or MHC IIlo TAMs (Supplementary Fig. S1B)

Summary

Introduction

To escape detection by the immune system, tumors foster an immunosuppressive environment and produce signals that subdue antitumor immune responses [1]. Tumor-associated macrophages (TAMs) are a heterogeneous population of myeloid cells that differentiate in the tumor microenvironment and become sensitized to tumor-derived suppressive signals [2]. TAMs, in turn, act to prevent local immune responses by inefficiently presenting antigen and generating suppressive signals such as IL10, indoleamine-pyrrole 2,3-dioxygenase (IDO), and TGFb that inhibit lymphocyte function and metabolism [3]. For adaptive immune responses to persist, tumor-infiltrating lymphocytes (TILs) must overcome a suppressive cytokine milieu and mechanisms of tolerance propagated by TAMs to successfully attack cancerous cells. CSF-1 (M-CSF) is a cytokine that supports differentiation, proliferation, and function of monocyte and macrophage populations [4].

Methods

Results

Conclusion