Tumor-derived GDF-15 blocks LFA-1 dependent T cell recruitment and suppresses responses to anti-PD-1 treatment

Abstract

Immune checkpoint blockade therapy is beneficial and even curative for some cancer patients. However, the majority don’t respond to immune therapy. Across different tumor types, pre-existing T cell infiltrates predict response to checkpoint-based immunotherapy. 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. In melanoma patients, GDF-15 serum levels strongly correlate with failure of PD-1-based immune checkpoint blockade therapy. Neutralization of GDF-15 improves both T cell trafficking and therapy efficiency in murine tumor models. 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.

Integrated immunogenomic analyses of high-grade serous ovarian cancer reveal vulnerability to combination immunotherapy

“…High expression of the integrin ITGB2 was previously shown to be associated with poor survival outcome [88], underscoring that high expression in TAMs is crucial. In contrast, ITGB2 is also associated with CD8+ T cells, as it encodes the beta chain of the LFA-1 protein, which has been shown to be essential in the assembly of the immune synapse or to influence lymphocyte extravasation and T-cell recruitment to the tumor and is regulated by GDF-15 [89]. This association is also underlined by a positive significant correlation of ITGB2 expression with M2 macrophages and, to a lesser extent, with estimated CD8+ T-cell infiltration in the TCGA cohort (Fig.…”

GPX3 supports ovarian cancer tumor progressionin vivoand promotes expression of GDF15

“…In gall bladder cancer, GDF15 has been shown to increase PD-L1 expression in a PI3K/Akt/Erk dependent manner to result in immune suppression (33). In addition, a recent study has shown that GDF15 suppresses responses to anti-PD1 immune check point therapy, as GDF-15 impairs T-cell endothelial adhesion and thus recruitment to the tumor, with T-reg recruitment being less affected (34). Thus, GPX3 and GDF15 appear to share similarities in their correlation to tumor immune cell signatures.…”

Exploring the Relationship Between Anorexia and Therapeutic Efficacy in Advanced Lung Cancer Treatment: A Retrospective Study

“…Anamorelin, an oral ghrelin agonist, has been shown to increase oral intake and muscle mass (body weight) but not to augment the therapeutic effects of chemotherapy [28]. In addition, basic research has shown that GDF-15 is associated with metastatic potential [29], proliferative capacity [30], therapeutic e cacy [31], and decreased survival [32,33]. Moreover, anti-GDF-15 antibodies are also expected to potentiate the action of immune checkpoint inhibitors [31].…”

“…In addition, basic research has shown that GDF-15 is associated with metastatic potential [29], proliferative capacity [30], therapeutic e cacy [31], and decreased survival [32,33]. Moreover, anti-GDF-15 antibodies are also expected to potentiate the action of immune checkpoint inhibitors [31]. Future prospective studies evaluating anorexia, weight loss, and treatment e cacy, including biomarker studies, are required to further provide further clarity.…”