Most cancer immunotherapies rely on the cytotoxic properties of CD8⁺ T cells, overshadowing the potential activity of CD4⁺ T cells targeting cancer cells. In this new study published in Nature Cancer, the team led by Philippe Bousso focused on CD4⁺ CAR T cells and showed that they significantly contribute to tumor regression through the long-range apoptotic effect of interferon-γ (IFN-γ).
In a mouse model of B cell lymphoma, they used intravital imaging of the bone marrow to observe the mode of action of CD4⁺ CAR T cells. It appears that the majority of killing events occur without direct contact with a cancer cell but at distance, through the production of IFN-γ which diffuses in the tumor microenvironment. Using different cell lines, they then showed that tumor sensitivity to IFN-γ could be a key factor in explaining the variability of CD4⁺ CAR T cell efficacy between patients.
These results were confronted to clinical data from a cohort of 63 patients with diffuse large B-cell lymphoma treated with CAR T cells at Hôpital Saint-Louis (Paris). Patients with high CD4⁺:CD8⁺ CAR T cell ratio showed stronger induction of IFN-γ. Among these patients, higher serum levels of IFN-γ were associated with significantly improved progression-free and overall survival, highlighting the antitumor activity of the cytokine produced by CD4⁺ CAR T cells and the potential of IFN-γ tumor sensitivity as a key parameter for personalized used of CAR T cell immunotherapies.
Tumor-intrinsic sensitivity to the pro-apoptotic effects of IFN-γ is a major determinant of CD4+ CAR T-cell antitumor activity, Nature Cancer, 29 mai 2023
Attack of a tumor by CAR T cells visualised using intravital imaging. Living cancer cells are shown in white, killed cancer cells in blue and CAR T cells in green. The white circles indicate the destruction of cancer cells during direct contact with CAR T cells, while the red circles indicate the destruction of cancer cells at a distance. © Morgane Boulch, Philippe Bousso / Institut Pasteur