Blockade of TGF beta drive hyper progression on Small Cell Lung Cancer
To uncover mechanisms underlying divergent outcomes in patients with small cell lung cancer (SCLC), a highly aggressive neuroendocrine malignancy, we performed bulk transcriptomics of pre-treatment tumor biopsies from patients enrolled in a clinical trial of bintrafusp alfa, a bifunctional fusion protein targeting PD-L1 and TGF-beta. We identified marked elevation of IFN-gamma signaling and MHC class II expression. In contrast, Hyperprogressive disease (HPD) was associated with systemic immune suppression, impaired cytotoxicity, and, unexpectedly, tumor-intrinsic activation of TGF-beta signaling and stemness. Functional studies confirmed that intact TGFbetaR2-mediated signaling is required for the hyperproliferative response to TGF-beta blockade, revealing a context-dependent tumor... (for more see dbGaP study page.)