Biology subjects

Rakhmilevich, A. L.

Publications and source records attributed to Rakhmilevich, A. L..

3 recordsLinked to original sources

bioRxiv2025

Immune-mediated Engagement of T Regulatory Cells with Tumor Cells Results in Trogocytosis and Tumor Cell Killing.

Despite advances in treatment, >50% of patients with advanced melanoma are unresponsive to current therapies. Using the B78-D14 melanoma model (GD2+/MHC-I-/MHC-II+), we can cure mice with a regimen that includes radiation therapy (RT) in combination with immunocytokine (IC; anti-GD2 monoclonal antibody linked to IL-2) while establishing immunological memory. We interrogated the role of T cells in the antitumor and memory responses following RT+IC. We show a requirement for CD4, but not CD8 T cells, to achieve both the initial and memory responses. Upon IC-induced cell-cell contact, subsets of CD4 T cells, including Foxp3 T regulatory cells, trogocytose GD2 from tumor cells, acquire cytotoxic granules, and kill tumor cells. These results were confirmed using human tumor cell lines. These findings reveal that CD4 T regulatory cells, upon immunologically-induced binding to tumor cells, can trogocytose tumor antigens and directly kill tumor cells, redefining their potential role in antitumor immunity.

cancer biology↗

bioRxiv2025

Divergent role of CD8 T cells with distinct metabolic phenotypes during curative radio-immunotherapy in hot versus cold tumors

Immunotherapy has potential for impactful cancer cures by empowering patients own immune cells. We developed a radio-immunotherapy regimen that can cure large immunologically hot and cold murine tumors. Here, we explored the divergent role of CD8 T cells during this radio-immunotherapy in contrasting hot colon carcinoma versus cold melanoma. We introduced an immunocompetent mouse model with mCherry-expressing CD8 T cells to provide cell tracking in vivo. We investigated single-cell function, metabolism, and gene expression temporal changes using flow cytometry, in vivo multiphoton imaging, single-cell RNA sequencing, and multiplexed immunofluorescence to determine the underlying mechanisms. We found that in contrast to the hot colon carcinoma model, CD8 T cells from the cold melanoma model do not drive tumor cures, despite getting activated, possibly due to a static oxidative metabolism and exhausted phenotype plus down regulation of tumor MHC-I expression. These findings have implications for improving immunotherapy response in immunologically cold cancers.

immunology↗

bioRxiv2024

Bispecific GD2 x B7-H3 Antibody Improves Tumor Targeting and Reduces Toxicity while Maintaining Efficacy for Neuroblastoma

The current treatment for neuroblastoma involves an immunotherapy regimen that includes a monoclonal antibody that recognizes disialoganglioside (GD2), expressed at high levels on neuroblastoma. GD2 is not present on most normal tissues but is expressed on nerves. Thus, anti-GD2 treatment causes substantial, dose-limiting, neuropathic pain. B7-H3 is overexpressed on multiple tumor types, including neuroblastoma, with minimal normal cell expression and is absent on nerves. We designed a bispecific antibody (bsAb) that requires simultaneous binding of these two tumor antigens to achieve tight-binding of tumor cells. Our preclinical research shows that when compared to an anti-GD2 monospecific antibody, the GD2xB7-H3 bsAb has improved tumor specificity with similar efficacy and reduced toxicity. Since this bsAb does not bind to nerves, it may be possible to administer increased or additional doses beyond the tolerable dose of monospecific anti-GD2 antibodies, which could improve therapeutic efficacy and quality of life for patients with neuroblastoma.

cancer biology↗