![]() T cell extravasation from the well-vascularized feto-maternal interface is strictly regulated. In mice, they only account for 3% of decidual leukocytes on embryonic day 8.5 9. Accordingly, T cells in placenta and decidua are functionally inhibited, and sparse. ![]() While detrimental in cancer, tolerance towards neoantigen-expressing cells is essential during pregnancy. Roadblocks to T cell infiltration (“T cell repellents”) are hence of major interest, both as biomarkers and as promising targets for therapeutic intervention. Successful responses to anti-PD-1 thus depend on freshly immigrating T cells 8. Further, tumor-infiltrating T cells gradually assume an epigenetically imprinted, irreversibly exhausted state 7. Instead, malignant cells often orchestrate a T cell-excluding microenvironment which confers resistance to immunotherapy 4, 5, 6. non-infiltrated (“cold”) phenotype of the tumor microenvironment is, however, hardly related to the availability of immunogenic (neo)antigens 3. Infiltration of cytotoxic immune effector cells into the tumor microenvironment is thus a prerequisite for successful immunotherapy 2. ![]() Responses require contact-dependent killing of cancer cells by immune cells. However, across 75 trials in 29 tumor types, only 1,568 out of 8,692 patients (18%) were classified as responders to anti-PD(L)1 monotherapy 1. Immune checkpoint blockade has achieved unprecedented durable responses in patients with advanced and metastatic cancer. Thus GDF-15, beside its known role in cancer-related anorexia and cachexia, emerges as a regulator of T cell extravasation into the tumor microenvironment, which provides an even stronger rationale for therapeutic anti-GDF-15 antibody development. Neutralization of GDF-15 improves both T cell trafficking and therapy efficiency in murine tumor models. In melanoma patients, GDF-15 serum levels strongly correlate with failure of PD-1-based immune checkpoint blockade therapy. Based on in vitro pharmacological studies, mouse models and analyses of human melanoma patients, we show that the cytokine GDF-15 impairs LFA-1/β2-integrin-mediated adhesion of T cells to activated endothelial cells, which is a pre-requisite of T cell extravasation. Across different tumor types, pre-existing T cell infiltrates predict response to checkpoint-based immunotherapy. However, the majority don’t respond to immune therapy. ![]() Immune checkpoint blockade therapy is beneficial and even curative for some cancer patients. Nature Communications volume 14, Article number: 4253 ( 2023) Tumor-derived GDF-15 blocks LFA-1 dependent T cell recruitment and suppresses responses to anti-PD-1 treatment ![]()
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