Abstract
Immune-checkpoint inhibitors (ICI) have transformed oncological therapy. Up to 20% of all non-small cell lung cancers (NSCLCs) show durable responses upon treatment with ICI, however, robust markers to predict therapy response are missing. Here we show that blood platelets interact with lung cancer cells and that PD-L1 protein is transferred from tumor cells to platelets in a fibronectin 1, integrin α5β1 and GPIbα-dependent manner. Platelets from NSCLC patients are found to express PD-L1 and platelet PD-L1 possess the ability to inhibit CD4 and CD8 T-cells. An algorithm is developed to calculate the activation independent adjusted PD-L1 payload of platelets (pPD-L1Adj.), which is found to be superior in predicting the response towards ICI as compared to standard histological PD-L1 quantification on tumor biopsies. Our data suggest that platelet PD-L1 reflects the collective tumor PD-L1 expression, plays important roles in tumor immune evasion and overcomes limitations of histological quantification of often heterogeneous intratumoral PD-L1 expression.
Highlights
Immune-checkpoint inhibitors (ICI) have transformed oncological therapy
To address whether the immune regulatory protein PD-L1 can be transferred from tumor cells to platelets, we co-incubated platelets obtained from healthy donors with four different non-small cell lung cancers (NSCLCs) tumor cell lines harboring varying expression levels of PD-L1 (NCI-H23, A549: PD-L1 low/ negative, NCI-H226, NCI-H460: PD-L1 positive) (Fig. 1a, b)
Co-incubation of platelets with all tumor cell lines resulted in platelet activation, as indicated by P-selectin (CD62P) induction (Fig. 1g), only coincubation with PD-L1 positive NCI-H226 and NCI-H460 cells resulted in an increased PD-L1 expression on the platelet surface (Fig. 1h)
Summary
Up to 20% of all non-small cell lung cancers (NSCLCs) show durable responses upon treatment with ICI, robust markers to predict therapy response are missing. An algorithm is developed to calculate the activation independent adjusted PD-L1 payload of platelets (pPD-L1Adj.), which is found to be superior in predicting the response towards ICI as compared to standard histological PD-L1 quantification on tumor biopsies. Evaluation of smoking history, tumor mutational burden (TMB), microsatellite instability (MSI), high expression of CTLA4, low expression of CX3CL1 and infiltration of CD8+ T cells within the tumor microenvironment (TME) seems to be superior in predicting therapy responses towards anti-PD-1/PD-L1 directed ICI13–15 when compared to histopathological PD-L1 quantification, these markers so far could not be translated into a robust and clinically easy to use biomarker signature. In our study pPD-L1Adj. is shown to be superior in predicting response to ICI when compared to immunohistochemistry-based quantification of PD-L1 on tumor biopsies
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