ABSTRACT
Adoptively transferred T cells and agents designed to block the CD47-SIRPα axis are promising cancer therapeutics that activate distinct arms of the immune system1,2. Here we administered anti-CD47 antibodies in combination with adoptively transferred T cells with the goal of enhancing antitumour efficacy but observed abrogated therapeutic benefit due to rapid macrophage-mediated clearance of T cells expressing chimeric antigen receptors (CARs) or engineered T cell receptors. Anti-CD47-antibody-mediated CAR T cell clearance was potent and rapid enough to serve as an effective safety switch. To overcome this challenge, we engineered the CD47 variant CD47(Q31P) (47E), which engages SIRPα and provides a 'don't eat me' signal that is not blocked by anti-CD47 antibodies. TCR or CAR T cells expressing 47E are resistant to clearance by macrophages after treatment with anti-CD47 antibodies, and mediate substantial, sustained macrophage recruitment to the tumour microenvironment. Although many of the recruited macrophages manifested an M2-like profile3, the combined therapy synergistically enhanced antitumour efficacy. Our study identifies macrophages as major regulators of T cell persistence and illustrates the fundamental challenge of combining T-cell-directed therapeutics with those designed to activate macrophages. It delivers a therapeutic approach that is capable of simultaneously harnessing the antitumour effects of T cells and macrophages, offering enhanced potency against solid tumours.
Subject(s)
CD47 Antigen , Immunotherapy, Adoptive , Neoplasms , T-Lymphocytes , Animals , Female , Humans , Male , Mice , Antigens, Differentiation/immunology , Antigens, Differentiation/metabolism , CD47 Antigen/genetics , CD47 Antigen/immunology , CD47 Antigen/metabolism , Cell Line, Tumor , Immunotherapy, Adoptive/methods , Macrophages/cytology , Macrophages/immunology , Neoplasms/immunology , Neoplasms/metabolism , Neoplasms/therapy , Receptors, Antigen, T-Cell/genetics , Receptors, Antigen, T-Cell/immunology , Receptors, Antigen, T-Cell/metabolism , Receptors, Chimeric Antigen/genetics , Receptors, Chimeric Antigen/immunology , Receptors, Chimeric Antigen/metabolism , Receptors, Immunologic/immunology , Receptors, Immunologic/metabolism , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , T-Lymphocytes/transplantation , Tumor Microenvironment/immunology , Antibodies/immunology , Antibodies/therapeutic use , Macrophage ActivationABSTRACT
Immune checkpoint blockade therapy (ICBT) has resulted in extended overall survival for some patients with certain types of cancer, most prominently including colorectal cancer (CRC) associated with microsatellite instability (MSI). However, most patients with CRC whose phenotypes have microsatellite stability (MSS) are unresponsive to ICBT. In efforts to understand the responsiveness of CRC tumors to ICBT, genotypic and phenotypic signatures of CRC tumors are now being investigated. The MSI and MSS classification has been clinically validated as helpful in predicting response vs nonresponse to ICBT in patients with CRC. Other potential predictive markers include mutational and neoantigen loads, T-cell receptor diversity, and the immune score system, all of which have mechanistic connections to ICBT response. These novel predictive signatures could provide unprecedented insights into patients with CRC associated with MSS. Clinical trials or prospective cohort studies using standardized methodologies for biomarker quantification should be illuminating. Further validation of these novel predictive signatures will be essential to tailoring treatment of patients whose CRC is most likely to respond to ICBT.
