Increasing the Efficacy of Chemotherapy by Rescuing the Innate Immune Response 2309649

Abstract

Abstract Introduction Despite advancements in immunotherapy, more than half of melanoma patients will either not respond or will later relapse after treatment with immune checkpoint blockade (ICB). For later-stage patients, chemotherapy is an essential treatment modality, but tumor intrinsic cell survival mechanisms and an immunosuppressive tumor microenvironment often limit efficacy. We recently discovered that by upregulating the secretion of Pros1, tumor cells limit the response of macrophages to chemotherapy released tumor Damage Associated Molecular Patterns (DAMPs). By pharmacologically inhibiting Ptp1b, a signaling intermediary downstream of the Mer receptor, macrophage responsiveness to DAMPs can be restored. This is associated with increased macrophage M1 polarization and immune infiltration, as well as a 40-80% decrease in tumor volume in multiple preclinical models. Methods We hypothesize that because Ptp1b inhibition prevents tumor suppression of DAMP responsiveness, combining Ptp1b inhibition may improve the efficacy of multiple chemotherapies, particularly those that promote necrotic and immunogenic cell death. To test this, macrophages were co-cultured with murine melanoma cells (B16F10) and cisplatin, doxorubicin, or dacarbazine in the presence or absence of Ptp1b inhibitor via transwell assay, after determining the relative amounts of apoptosis/necrosis produced by each chemotherapy. Results Preliminary results indicate that Ptp1b inhibition significantly increases macrophage pro-inflammatory gene expression by 7.5-fold in a setting of chemotherapy-induced tumor DAMP release. This indicates that inhibiting Ptp1b could synergistically improve chemotherapy effectiveness. Conclusion As Ptp1b inhibitors have a reasonable safety profile based on multiple clinical trials, combining Ptp1b inhibiting drugs with chemotherapy may be a novel way to restore the innate immune response during treatment while also improving patient outcomes. Funding Source NCI- RO1 CA262241(Ubil) Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)