Cancer immunotherapy: GDF-15’s role in Anti-PD-1 resistance

The focus of this study is on Growth Differentiation Factor-15 (GDF-15), a cytokine known for its critical role in feto-maternal tolerance, which has now been found to be hijacked by tumours to evade immune attack. We will explore how GDF-15 impacts the tumour microenvironment and hinders the infiltration of T cells into the tumour, as well as the implications of neutralising GDF-15 to reverse its inhibitory effects and sensitise tumours to anti-PD-1 treatment.

What is the central factor identified in the preclinical data that contributes to anti-PD-1 resistance in cancer immunotherapy?

Growth Differentiation Factor-15 (GDF-15) is a cytokine known for its essential function in feto-maternal tolerance, an immunosuppressive mechanism that protects the foetus from the mother’s immune system.  Tumours have hijacked GDF-15 and overexpress it to protect themselves from immune attack. The current study is the first to demonstrate a mechanistic link between tumour-produced GDF-15 and the LFA-1/ICAM-1 cell adhesion axis, resulting in impaired infiltration of T cells into the tumour microenvironment. Neutralising GDF-15 with CatalYm’s anti-GDF-15 antibody visugromab was shown to reverse its inhibitory effects and to re-sensitise tumours to anti-PD-1 treatment, achieving commensurate survival benefit of anti-GDF-15-anti-PD-1 combination therapy in vivo.

How does GDF-15 impact the tumour microenvironment and the infiltration of T cells into the tumour?

Infiltration of immune cells into tissues follows a cascade of events, namely rolling, activation, adhesion and transmigration, which are mediated by different molecules. Adhesion is mediated via Lymphocyte function-associated antigen (LFA)-1 and Intercellular adhesion molecule (ICAM)-1, which are expressed on the surface of T cells and endothelial cells, respectively. Cancer-derived GDF-15, which is highly overexpressed in more than 50 percent of human solid tumours, blocks T cell recruitment into the tumour microenvironment by inhibiting activation of Lymphocyte function-associated antigen (LFA)-1 which remains unable to interact with Intercellular adhesion molecule (ICAM)-1. By keeping LFA-1 in an inactive conformation, GDF-15 prevents the T cell’s transmigration from the blood vessel to the tumour site (see also graphic below). With this mechanism, GDF-15 enables the tumour to evade being detected and destroyed by immune cells.

What are the implications of neutralising GDF-15 in reversing inhibitory effects and sensitising tumours to anti-PD-1 treatment in the preclinical study?

The study showed that neutralising GDF-15 with CatalYm’s anti-GDF-15 antibody improved T cell infiltration into tumours in mouse models. T-cell infiltration is a prerequisite for responses to checkpoint inhibitors. Combined with a PD-1 inhibitor, it increased tumour clearance and survival with a synergistic effect.

Based on the published data, what is the potential role of GDF-15 as a predictive biomarker for the response to anti-PD-1 therapy and overall survival in melanoma patients?

Microarray analysis of brain metastases from melanoma patients demonstrated a negative correlation between GDF-15 serum levels and T cell infiltration, the latter being a predictive marker for treatment outcome in this indication. These findings were mirrored in the clinical results from an analysis of two metastatic melanoma patient cohorts who received anti-PD-1 treatment: patients with responses and disease control had significantly lower GDF-15 serum levels (measured before treatment start), while none of the patients with elevated GDF-15 levels showed a lasting response. Together with the fact that GDF-15 is overexpressed in more than 50 percent of all solid tumours, these results highlight GDF-15 as a predictive biomarker for failure of immune checkpoint blockade.

Can you explain the significance of the LFA-1/ICAM-1 cell adhesion axis in relation to T cell recruitment into the tumour microenvironment and its relevance to immune checkpoint blockade?

The interaction between LFA-1/ICAM-1 is known to be essential for the extravasation of T cells from the blood vessels into the surrounding tissue.¹ Several previous publications demonstrated the importance of this axis for a successful infiltration of T cells into the microenvironment of solid tumours,² a key factor for the effective destruction of tumour cells and a prerequisite for the success of immune checkpoint blockade therapies, such as anti-PD-(L)1 antibodies.

The results from our study add to these data, demonstrating that tumour-produced GDF-15 blocks LFA-1-dependent T cell recruitment into the tumour microenvironment and, conversely, that blockade of GDF-15 with our anti-GDF-15 antibody visugromab reenables T cell infiltration into tumours in mouse models. Moreover, a combined treatment with a PD-1 inhibitor showed a synergistic effect on tumour clearance and survival, highlighting the synergistic clinical potential of this approach.

How does the preclinical data contribute to the understanding of GDF-15 as a central factor of innate resistance to PD-1 treatment in solid tumour patients?

The findings in this publication reveal a new cancer resistance mechanism of tumour cells that can be either innate or acquired following cancer treatment. “Innate resistance,” in this case, means that cancer cells from the beginning have higher levels of GDF-15 that allow them to circumvent immunotherapies and, therefore, prevent treatment success. Increased GDF-15 levels can, however, also be a reaction to cancer therapy due to tumor cell stress, representing an adaptive mechanism that cancer cells use upon therapeutic pressure to ensure their survival. This mechanism can be triggered by different types of therapy, such as chemotherapy or PD-(L)1 blockage. Our data contribute and expand this body of knowledge by demonstrating that neutralisation of GDF-15 can reverse this immunosuppressive mechanism, with a synergistic effect for the combination of anti-GDF-15 and anti-PD-1 antibodies.

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