Platelets subvert antitumor efficacy of T cell-recruiting bispecific antibodies

Abstract

T cell-based immunotherapy, for example, with T cell-recruiting bispecific antibody (bsAb), has revolutionized oncological treatment. However, many patients do not respond to treatment, and long-term remissions are still rare. Several tumor immune evasion mechanisms have been reported to counteract efficiency of T cell-engaging therapeutics. Platelets largely affect cancer pathophysiology by mediating tumor invasion, metastasis, and immune evasion. On treatment of patients in a clinical trial with a PSMA×CD3 bsAb (NCT04104607), we observed profound treatment-associated platelet activation, mirrored by a decrease of total platelet count. On modeling the treatment setting, we found that platelet activation significantly reduced bsAb-mediated CD4+ and CD8+ T-cell reactivity as revealed by impaired T-cell degranulation, secretion of perforin, and ultimately, inhibition of target cell lysis. This effect occurred in a transforming growth factor beta (TGF-β)-dependent manner and was not restricted to PSMA×CD3 bsAb, but rather observed with various CD3-directed bispecific constructs, including the approved CD19×CD3 bsAb blinatumomab. BsAb-mediated T-cell reactivity could be restored by platelet inhibition and specifically by blocking the TGF-β axis. Together, our findings demonstrate that platelets undermine the efficacy of T cell-recruiting bsAb and identify modulation of platelet function as a means to reinforce the effectiveness of bsAb treatment.

Revealing profile of cancer-educated platelets and their factors to foster immunotherapy development

“…Although T cell-based immunotherapy based on T cell-recruiting bispecific antibody (bsAb) made important progress in immunooncology therapies, many patients do not respond to treatment. Thus, a clinical study NCT04104607 [ 85 ] has shown that prostate-specific membrane antigen (PSMA) × CD3 bsAb decreased total platelet amount, while platelet activation was present. Specifically, platelet activation impaired bsAb-mediated CD4 + and CD8 + T-cell reactivity, leading to inhibition of tumor cell lysis, while blockade of TGF-β could restored T-cell reactivity [ 85 ].…”

“…Thus, a clinical study NCT04104607 [ 85 ] has shown that prostate-specific membrane antigen (PSMA) × CD3 bsAb decreased total platelet amount, while platelet activation was present. Specifically, platelet activation impaired bsAb-mediated CD4 + and CD8 + T-cell reactivity, leading to inhibition of tumor cell lysis, while blockade of TGF-β could restored T-cell reactivity [ 85 ]. Interestingly, platelets increase PD-L1 on ovarian tumor cells both directly (contact-dependent via NF-κB signaling) and indirectly (via TGF-β released from platelets through TGF-βR1/Smad signaling) [ 40 ].…”

Platelet-monocyte aggregates: molecular mediators of thromboinflammation

“…Since NPA and MPA are found to be simultaneously elevated in proinflammatory conditions ( 129 ), activated platelet induce a prothrombogenic state via both leukocyte subpopulations by enhancing their respective inflammatory response in vivo . In contrast, while the magnitude of circulating lymphocyte-platelet aggregates does not change in inflammatory, thrombotic, and atherosclerotic diseases, platelet-lymphocyte interaction has been delineated to exert a specific role in cancer: For example, platelets attenuated T cell activity in cancer patients ex vivo ( 130 ), and promoted tumor progression via suppression of CD8 T cells in murine cancer models ( 131 ).…”

Interactions between Platelets and Tumor Microenvironment Components in Ovarian Cancer and Their Implications for Treatment and Clinical Outcomes

“…On the other hand, other studies show that platelets induce the expression of PD-L1 in cancer cells [14,270], and reducing platelet counts via an antiplatelet agent treatment can minimize the effectiveness of immunotherapy [14]. In addition, platelet-derived TGF-β reduces the efficacy of T cell recruitment via bispecific antibody (BsAb)-based immunotherapy [271] in ovarian cancer [272]. Immune checkpoint inhibitors administered with VEGF inhibitors have been shown to improve the efficacy of BsAbs in ovarian cancer [273].…”