Using an immunocompetent mouse B cell lymphoma model, Boulch and Cazaux et al. studied interactions of anti-CD19 CD4+ and CD8+ CAR T cells (CAR4 and CAR8) with the TME. Their results showed CAR T cell-derived IFNγ caused wide-ranging effects including promoting host cell immunity by increasing endogenous T and NK cell activity, sustaining CAR T cell cytotoxicity, enabling host IL-12 production, and promoting tumor regression. CAR T cell subsets had overlapping and complementary roles, as CAR8 cells were more capable of lysing tumor cells in vivo and CAR4 cells recruited and activated immune cells more efficiently.
Contributed by Katherine Turner
ABSTRACT: Chimeric antigen receptor (CAR) T cell therapy relies on the activity of a large pool of tumor-targeting cytotoxic effectors. Whether CAR T cells act autonomously or require interactions with the tumor microenvironment (TME) remains incompletely understood. Here, we report an essential cross-talk between CAR T cell subsets and the TME for tumor control in an immunocompetent mouse B cell lymphoma model of anti-CD19 CAR T cell therapy. Using single-cell RNA sequencing, we revealed substantial modification of the TME during CAR T cell therapy. Interferon-γ (IFN-γ) produced by CAR T cells not only enhanced endogenous T and natural killer cell activity but was also essential for sustaining CAR T cell cytotoxicity, as revealed by intravital imaging. CAR T cell-derived IFN-γ facilitated host interleukin-12 production that supported host immune and CAR T cell responses. Compared with CD8+ CAR T cells, CD4+ CAR T cells were more efficient at host immune activation but less capable of direct tumor killing. In summary, CAR T cells do not act independently in vivo but rely instead on cytokine-mediated cross-talk with the TME for optimal activity. Invigorating CAR T cell interplay with the host represents an attractive strategy to prevent relapses after therapy.
Author Info: (1) Dynamics of Immune Responses Unit, Equipe Labellise Ligue Contre le Cancer, Institut Pasteur, INSERM U1223, 75015 Paris, France. University Paris Diderot, Sorbonne Paris Cit, P
Author Info: (1) Dynamics of Immune Responses Unit, Equipe Labellise Ligue Contre le Cancer, Institut Pasteur, INSERM U1223, 75015 Paris, France. University Paris Diderot, Sorbonne Paris Cit, Paris, France. (2) Dynamics of Immune Responses Unit, Equipe Labellise Ligue Contre le Cancer, Institut Pasteur, INSERM U1223, 75015 Paris, France. marine.cazaux@aphp.fr philippe.bousso@pasteur.fr. University Paris Diderot, Sorbonne Paris Cit, Paris, France. (3) Hub de Bioinformatique et Biostatistique - Dpartement Biologie Computationnelle, Institut Pasteur, Paris, France. (4) Dynamics of Immune Responses Unit, Equipe Labellise Ligue Contre le Cancer, Institut Pasteur, INSERM U1223, 75015 Paris, France. University Paris Diderot, Sorbonne Paris Cit, Paris, France. (5) Dynamics of Immune Responses Unit, Equipe Labellise Ligue Contre le Cancer, Institut Pasteur, INSERM U1223, 75015 Paris, France. (6) Dynamics of Immune Responses Unit, Equipe Labellise Ligue Contre le Cancer, Institut Pasteur, INSERM U1223, 75015 Paris, France. (7) Dynamics of Immune Responses Unit, Equipe Labellise Ligue Contre le Cancer, Institut Pasteur, INSERM U1223, 75015 Paris, France. (8) Dynamics of Immune Responses Unit, Equipe Labellise Ligue Contre le Cancer, Institut Pasteur, INSERM U1223, 75015 Paris, France. (9) Dynamics of Immune Responses Unit, Equipe Labellise Ligue Contre le Cancer, Institut Pasteur, INSERM U1223, 75015 Paris, France. marine.cazaux@aphp.fr philippe.bousso@pasteur.fr.
