Biology subjects

Trisal, M.

Publications and source records attributed to Trisal, M..

4 recordsLinked to original sources

bioRxiv2026

Systems serology of responses against tumor antigens in ovarian cancer reveal disrupted Fc-mediated immunity

High-grade serous ovarian cancer (HGSOC) represents 75% of ovarian cancer cases and 80% of deaths, with most patients relapsing despite initial treatment response. The limited effectiveness of immunotherapies in HGSOC indicates urgent need for novel therapeutic approaches. HGSOC patients produce tumor-binding autoantibodies (TBAs) with high tumor selectivity. Since effective antibody-mediated tumor cell killing requires Fc domain interactions with immune cells, we hypothesized that, although TBAs recognize tumor cells, they might still poorly elicit cell killing responses. Using a systems serology approach, we profiled TBA subclass and biophysical interactions with Fc receptors in HGSOC, comparing them to antiviral antibody responses. TBAs were consistently identified within ascites and serum and were heterogeneous in subclass composition. However, TBAs consistently lacked the capacity to bind Fc{gamma}RIIIa despite abundant interaction with Fc{gamma}RIIa and poorly elicited antibody-dependent cellular cytotoxicity, suggesting their Fc features prevent cell killing responses. Restoring Fc{gamma}RIIIa interaction may be a promising therapeutic approach in HGSOC. HighlightsO_LITBAs in ovarian carcinoma patients consistently lack interaction with Fc{gamma}RIIIa C_LIO_LIAscites- and serum-derived TBAs have heterogeneous subclass composition C_LIO_LISystems analysis shows complex serologic differences between TBAs and antiviral responses C_LIO_LIPatient-expressed TBAs demonstrate little antibody-dependent cellular cytotoxicity C_LI

cancer biology↗

bioRxiv2022

Inhibition of CHK2 dependent DNA damage response suppresses Zika virus infection through a STING dependent mechanism

Zika virus (ZIKV) is a mosquito-borne flavivirus that causes neurological disorders and microcephaly. Recent research has shown that ZIKV causes cell cycle arrest and DNA damage response in neuronal progenitor cells that potentially leads to congenital neurodevelopmental defects. However, the specific role of regulators that control DNA damage response to ZIKV infection and the related mechanisms remain largely unknown. Here through both in vitro and in vivo studies, we observe that ZIKV induces DNA damage response in both human cell line and mouse embryo. When CHK2 dependent DNA damage response pathway is inhibited by a small molecule inhibitor or genetic deletion, ZIKV production is reduced and the embryonic developmental defects are rescued. Furthermore, we demonstrate that in ZIKV infected Chk2-/- mice, the reduced viral load correlates with elevated antiviral innate immune response which is found to be dependent on the STING signaling pathway. Collectively, our study reveals a specific role of CHK2 for ZIKV infection and pathogenesis, demonstrating a mechanism that inhibition of the CHK2 axis suppresses ZIKV infection through the STING-dependent antiviral pathway, thus providing a new therapeutic strategy against ZIKV. These findings also suggest the intriguing possibility that ZIKV evolved to orchestrate DNA damage response factors to create a beneficial environment for its infection in the host cells.

immunology↗

bioRxiv2021

Durability of immune responses to the BNT162b2 mRNA vaccine

The development of the highly efficacious mRNA vaccines in less than a year since the emergence of SARS-CoV-2 represents a landmark in vaccinology. However, reports of waning vaccine efficacy, coupled with the emergence of variants of concern that are resistant to antibody neutralization, have raised concerns about the potential lack of durability of immunity to vaccination. We recently reported findings from a comprehensive analysis of innate and adaptive immune responses in 56 healthy volunteers who received two doses of the BNT162b2 vaccination. Here, we analyzed antibody responses to the homologous Wu strain as well as several variants of concern, including the emerging Mu (B.1.621) variant, and T cell responses in a subset of these volunteers at six months (day 210 post-primary vaccination) after the second dose. Our data demonstrate a substantial waning of antibody responses and T cell immunity to SARS-CoV-2 and its variants, at 6 months following the second immunization with the BNT162b2 vaccine. Notably, a significant proportion of vaccinees have neutralizing titers below the detection limit, and suggest a 3rd booster immunization might be warranted to enhance the antibody titers and T cell responses.

immunology↗

bioRxiv2021

Adjuvanting a subunit SARS-CoV-2 nanoparticle vaccine to induce protective immunity in non-human primates

The development of a portfolio of SARS-CoV-2 vaccines to vaccinate the global population remains an urgent public health imperative. Here, we demonstrate the capacity of a subunit vaccine under clinical development, comprising the SARS-CoV-2 Spike protein receptor binding domain displayed on a two-component protein nanoparticle (RBD-NP), to stimulate robust and durable neutralizing antibody (nAb) responses and protection against SARS-CoV-2 in non-human primates. We evaluated five different adjuvants combined with RBD-NP including Essai O/W 1849101, a squalene-in-water emulsion; AS03, an alpha-tocopherol-containing squalene-based oil-in-water emulsion used in pandemic influenza vaccines; AS37, a TLR-7 agonist adsorbed to Alum; CpG 1018-Alum (CpG-Alum), a TLR-9 agonist formulated in Alum; or Alum, the most widely used adjuvant. All five adjuvants induced substantial nAb and CD4 T cell responses after two consecutive immunizations. Durable nAb responses were evaluated for RBD-NP/AS03 immunization and the live-virus nAb response was durably maintained up to 154 days post-vaccination. AS03, CpG-Alum, AS37 and Alum groups conferred significant protection against SARS-CoV-2 infection in the pharynges, nares and in the bronchoalveolar lavage. The nAb titers were highly correlated with protection against infection. Furthermore, RBD-NP when used in conjunction with AS03 was as potent as the prefusion stabilized Spike immunogen, HexaPro. Taken together, these data highlight the efficacy of the RBD-NP formulated with clinically relevant adjuvants in promoting robust immunity against SARS-CoV-2 in non-human primates.

immunology↗