Biology subjects

Ybarra, J.

Publications and source records attributed to Ybarra, J..

3 recordsLinked to original sources

bioRxiv2025

TLR2 signaling uniquely destabilizes tumor Tregs to promote cancer immunotherapy

A fundamental principle of immune responses is that innate immunity promotes adaptive immunity, but in the context of cancer immunity, the importance of innate receptor signaling is poorly defined. To study how Toll-like receptor (TLR) signaling contributes to cancer immunity, we used an attenuated strain of Listeria monocytogenes (Lm) that inhibits tumor growth in mice. We found that Lm stimulation of TLR2, but not TLR5 or TLR9, was essential for tumor control. As expected, TLR2 supported the priming of Lm-specific T cells in lymphoid tissues. However, TLR2 signaling in innate immune cells within tumors also destabilized Foxp3 expression in regulatory T cells (Tregs), a function that was not mediated by other TLRs. Reduced Treg function promoted tumor antigen cross-presentation by DC1s to enhance the functionality of recalled tumor-specific CD8+ T cells directly within tumors. These findings reveal a unique capacity for TLR2 signaling to diminish immunosuppression and promote cancer immunity.

immunology↗

bioRxiv2025

In vivo validation of the palmitoylation cycle as a therapeutic target in NRAS-mutant cancer

Ras proteins are functionally dependent on one or more lipid modifications.1,2 The dynamic palmitoylation of N-Ras by DHHC palmitoyl acyltransferases and depalmitoylation by ABHD17 serine hydrolases is essential for the growth of NRAS-mutant acute myeloid leukemia (AML) cells.3-6 Here we show that ABD778, an in vivo-active ABHD17 inhibitor, selectively reduces the growth of NRAS-mutant AML and melanoma cell lines and is synergistic with the MEK inhibitor PD0325901 (PD901; mirdametinib). Mechanistically, ABD778 and PD901 induce deep and durable suppression of mitogen activated protein kinase (MAPK) pathway activation. Co-treatment extended the survival of mice transplanted with NrasG12D AMLs, which acquired by-pass mutations at relapse that conferred drug resistance and restored MAPK activation. ABD778 augmented the anti-leukemia activity of PI3 kinase, pan-Ras tri-complex, and FLT3 inhibitors, and restored gilteritinib sensitivity in a patient-derived xenograft model of FLT3 inhibitor resistance. These studies validate the palmitoylation cycle as a therapeutic target in NRAS-mutant cancers.

cancer biology↗

bioRxiv2024

Cellular mechanisms underlying beneficial versus detrimental effects of bacterial antitumor immunotherapy

Bacteria engineered to express tumor antigens as a cancer vaccine have yielded mixed results. Here, we utilized an attenuated strain of Listeria monocytogenes ({Delta}actA, Lm) that does not express tumor antigen to explore the immunological response to Listeria itself in the context of intravenous (IV), intratumoral (IT), or a combination of IV+IT administration into tumor-bearing mice. Unexpectedly, we found that Lm persisted in tumors of immune competent mice, regardless of the administration route. While IT Lm alone led to the recruitment of immunosuppressive immune cells that promoted tumor growth, IV Lm followed by IT Lm controlled tumor growth. IV Lm vaccination generated a pool of anti-Lm cytotoxic CD8 T cells that killed Lm-infected non-tumor cells to control tumor growth both indirectly, by limiting cancer cell proliferation, and directly, by enhancing tumor-specific T cell responses. Our findings reveal a differential impact of IT Lm administration on tumor progression that depends on the presence of anti-Lm CD8 T cells, which alone are sufficient to promote therapeutic efficacy.

immunology↗