COVID-19, the disease caused by the SARS-CoV-2 virus, can progress to multi-system organ failure and viral sepsis characterized by respiratory failure, arrhythmias, thromboembolic complications, and shock with high mortality. Autopsy and pre-clinical evidence implicate aberrant complement activation in endothelial injury and organ failure. Erythrocytes express complement receptors and are capable of binding immune complexes; therefore, we investigated complement activation in COVID-19 patients using erythrocytes as a tool to diagnose complement activation. We discovered enhanced C3b and C4d deposition on erythrocytes in COVID-19 sepsis patients and non-COVID sepsis patients compared with healthy controls, supporting the role of complement in sepsis-associated organ injury. Our data suggest that erythrocytes may contribute to a precision medicine approach to sepsis and have diagnostic value in monitoring complement dysregulation in COVID-19-sepsis and non-COVID sepsis and identifying patients who may benefit from complement targeted therapies.
Patients with metastatic HER2 breast cancer (MBC) often become resistant to HER 2 targeted therapy and have recurrence of disease. The Panacea trial suggested that HER2 MBC patients were more likely to respond to checkpoint therapy if TIL were present or if tumor expressed PD-L1. We assessed whether type I polarized dendritic cells (DC1) could improve checkpoint therapy in a preclinical model of HER2
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breast cancer. TUBO bearing mice were vaccinated with either MHC class I or class II HER2 peptide pulsed DC1 (class I or class II HER2-DC1) concurrently or sequentially with administration of anti-PD-1 or anti-PDL1. Infiltration of tumors by immune cells, induction of anti-HER2 immunity and response to therapy was evaluated. Class I or class II HER2-DC1 vaccinated mice generated anti-HER2 CD8 or CD4+ T cell immune responses and demonstrated delayed tumor growth. Combining both MHC class I and II HER2-pulsed DC1 did not further result in inhibition of tumor growth or enhanced survival compared to individual administration. Interestingly class II HER2-DC1 led to both increased CD4 and CD8 T cells in the tumor microenvironment while class I peptides typically resulted in only increased CD8 T cells. Anti-PD-1 but not anti-PD-L1 administered sequentially with class I or class II HER2-DC1 vaccine could improve the efficacy of HER2-DC1 vaccine as measured by tumor growth, survival, infiltration of tumors by T cells and increase in systemic anti-HER2 immune responses. Depletion of CD4+ T cells abrogated the anti-tumor efficacy of combination therapy with class II HER2-DC1 and anti-PD-1, suggesting that tumor regression was CD4 dependent. Since class II HER2-DC1 was as effective as class I, we combined class II HER2-DC1 vaccine with anti-rat neu antibodies and anti-PD-1 therapy. Combination therapy demonstrated further delay in tumor growth, and enhanced survival compared to control mice. In summary, Class II HER2-DC1 drives both a CD4 and CD8 T cell tumor infiltration that leads to increased survival, and in combination with anti-HER2 therapy and checkpoint blockade can improve survival in preclinical models of HER2 positive breast cancer and warrants exploration in patients with HER2 MBC.
BackgroundWe have developed a new approach to reduce the serum interference for ELISA. The purpose of this study is to investigate if we can use the optimized ELISA (MBB-ELISA) to detect serum soluble HER2/neu (sHER2) in early stage primary breast cancer and monitor its change during treatments.FindingsWe collected sera preoperatively from 118 primary breast cancer patients. Serum samples were also collected sequentially from a subset of patients during and after adjuvant treatment. sHER2 in these samples was measured by the MBB-ELISA. Only 16.7 % of tissue HER2 (tHER2) positive patients had significantly elevated sHER2 levels in serum. Interestingly, sera of some patients with tHER2 negative tumors, including those that were 2+ by IHC but negative by FISH, demonstrated slightly elevated sHER2 levels. Multivariate analysis demonstrated that patients with elevated sHER2 (> = 7 ng/ml) had significantly worse disease free survival. During treatments, sHER2 levels consistently fell in response to adjuvant therapies. Nevertheless, in all 4 patients who developed metastases, a steady rise in sHER2 levels was noted before metastatic disease became clinically evident.ConclusionsFor early stage breast cancers, sHER2 is a poor biomarker to predict tHER2 status, but may have value to supplement tissue tests to identify patients with HER2 tumors. Our results also suggest that sHER2 is worth further study as a biomarker to monitor breast cancer patients during treatments.
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