Unexpected PD‐L1 immune evasion mechanism in TNBC, ovarian, and other solid tumors by DR5 agonist antibodies

Abstract

Lack of effective immune infiltration represents a significant barrier to immunotherapy in solid tumors. Thus, solid tumor‐enriched death receptor‐5 (DR5) activating antibodies, which generates tumor debulking by extrinsic apoptotic cytotoxicity, remains a crucial alternate therapeutic strategy. Over past few decades, many DR5 antibodies moved to clinical trials after successfully controlling tumors in immunodeficient tumor xenografts. However, DR5 antibodies failed to significantly improve survival in phase‐II trials, leading in efforts to generate second generation of DR5 agonists to supersize apoptotic cytotoxicity in tumors. Here we have discovered that clinical DR5 antibodies activate an unexpected immunosuppressive PD‐L1 stabilization pathway, which potentially had contributed to their limited success in clinics. The DR5 agonist stimulated caspase‐8 signaling not only activates ROCK1 but also undermines proteasome function, both of which contributes to increased PD‐L1 stability on tumor cell surface. Targeting DR5‐ROCK1‐PD‐L1 axis markedly increases immune effector T‐cell function, promotes tumor regression, and improves overall survival in animal models. These insights have identified a potential clinically viable combinatorial strategy to revive solid cancer immunotherapy using death receptor agonism.

Multiomic analysis identifies CPT1A as a potential therapeutic target in platinum-refractory, high-grade serous ovarian cancer

“…Additionally, our preclinical models do not capture the influence of the immune system and tumor microenvironment on platinum responsiveness. Considering recent observations that cytotoxic death of ovarian cells could stabilize PD-L1 or other negative immune regulatory receptors, 161 a combinatorial strategy targeting immune-negative regulators could be required for the CPT1A inhibitors to be fully effective in patients. Finally, although we chose to focus functional studies on CPT1A, we hope this high-quality dataset will prove a valuable resource to the research community to stimulate additional studies to advance our understanding of platinum resistance.…”

A patch of positively charged residues regulates the efficacy of clinical DR5 antibodies in solid tumors

“…Native DR5 immunoprecipitation studies with clinical antibodies Native DR5 immunoprecipitation studies with clinical antibodies were performed as described earlier (Mondal et al, 2021). Briefly, cells were cultured in 10 cm tissue culture dishes for 24 hours prior to treatment.…”

“…The antibody doses were given two or three times per week as indicated in text and figure legends. Tumors were measured in two dimensions using a caliper as described previously (Graves et al, 2014;Mondal et al, 2021;Shivange et al, 2018;Wilson et al, 2011). Tumor volume was calculated using the formula: V = 0.5axb 2 , where a and b are the long and the short diameters of the tumor, respectively.…”

A Feasible Alternative Strategy Targeting Furin Disrupts SARS-CoV-2 Infection Cycle

“…4L , middle blot) cellular lysates. We also made use of Pradaxa (a blood thinner small molecular inhibitor) targeting antibody idarucizumab ( 20 ) which has been exclusively used in our lab as a control molecule ( 20 , 34 ). When tested, idarucizumab-FuG1 did not immunoprecipitated furin ( Fig.…”

“…The sequence sources of various spike-targeting antibodies used in this study is provided. Additional antibodies such as farletuzumab, KMTR2, avelumab, idarucizumab clones has been published by our research group and are described earlier ( 20 , 34 , 53 ). Generation of linkered IgG1 has been described earlier by our group, see Fig.…”