Biology subjects

Bachanova, V.

Publications and source records attributed to Bachanova, V..

3 recordsLinked to original sources

bioRxiv2025

Functional genomics and tumor microenvironment analysis reveal prognostic biological subtypes in Mantle cell lymphoma

Mantle cell lymphoma (MCL) is a genetically and clinically heterogeneous B-cell malignancy. We studied two MCL cohorts with differing treatment patterns: one enriched for immunochemotherapy, the other for chemotherapy alone. TP53 alterations were consistently associated with poor prognosis, whereas ATM mutations correlated with improved outcomes following rituximab-based chemotherapy. Based on recurrent genetic events, six clusters were identified and refined into three prognostic groups: high-risk (TP53 mutations and deletions at 17p13.3, 13q14.2, and 19p13.3), intermediate-risk (ATM and epigenetic regulator mutations, or gains at 8q/17q/15q), and low-risk (lacking TP53 alterations, rare ATM mutations without 11q deletions, gains at 3q, deletions at 6q). Transcriptomic analysis revealed enrichment of proliferation, metabolism-promoting gene signatures in high-risk; angiogenesis and NOTCH signaling in intermediate-risk; and proinflammatory-related (i.e., IFN, TNF) in low-risk MCLs. Multi-proteomic spatial profiling using imaging mass cytometry (IMC) demonstrated enrichment of CD8 T cells with high expression of exhaustion markers and dominant population of myeloid cells skewed toward an M2-like phenotype. Compared to ATM-perturbed tumors, TP53-perturbed tumors exhibited enriched SOX11 tumor cells and enhanced tumor-immune cell interactions. Functional analysis revealed that p53 represses BCR signaling through PTPN6 activation. Collectively, these findings highlight distinct molecular and immune landscapes and reveal therapeutic vulnerabilities in high-risk TP53-altered MCL.

cancer biology↗

bioRxiv2024

Leukemia escapes immunity by imposing a Type-1 regulatory program on neoantigen-specific CD4+ T cells.

The significance of endogenous immune surveillance in acute lymphoblastic leukemia (ALL) remains controversial. Using clinical B-ALL samples and a novel mouse model, we show that neoantigen-specific CD4+ T cells are induced to adopt type-1 regulatory (Tr1) function in the leukemia microenvironment. Tr1s then inhibit cytotoxic CD8+ T cells, preventing effective leukemia clearance. Leukemic cells induce Tr1s by phenocopying hematopoietic stem cells, which normally are subject to effective surveillance by this CD4+ subset. This mechanism effectively redirects Tr1 cells from a role in preventing cancer to maladaptively promoting clinical relapse. In mouse models, inhibition of Tr1 expansion with IL10 receptor (IL10R) blockade is insufficient to improve leukemia control. In contrast, combined therapy with a cytotoxic agent and anti-PDL1 blockade eradicated measurable residual disease. This correlates with polarization of the neoantigen-specific CD4+ T-cell population from Tr1 towards Th1 states. Our findings uncover a mechanism that enables leukemic relapse and resolves existing controversies on the role of immune surveillance towards this cancer type. Therapeutic polarization of neoantigen-specific CD4+ T cells towards Th1 states may improve contemporary immune therapies by reshaping the immune microenvironment towards states permissive for cytotoxic attack of residual leukemia. Key PointsO_LIB-ALL induces neoantigen-specific CD4+ T cells to adopt Type-1 regulatory states, which protect leukemic cells from immune pressure. C_LIO_LIRepolarizing neoantigen-specific CD4+ T-cells towards Th1 states eradicates measurable residual disease. C_LI

cancer biology↗

bioRxiv2022

Myeloid reprogramming by JAK inhibition enhances checkpoint blockade therapy

Unleashing anti-tumor T cell activity by checkpoint inhibition is effective in many cancer patients but clinical response rates remain limited. Myeloid derived suppressor cells erode antitumor lymphocyte numbers and function, and correlate with resistance to checkpoint inhibitors. By screening small molecule libraries, we identified JAK inhibitors ability to rescue T cell function. Despite its documented immune suppressive properties, the prototypical JAK inhibitor ruxolitinib enhanced the efficacy of immune checkpoint blockade in cancer. This effect correlated with loss of suppressive gene expression, and acquisition of immunostimulatory molecular markers and T cell stimulatory activity in myeloid cells. In preclinical models, ruxolitinib significantly improved the function and increased the total numbers of activated tumor-infiltrating NK and CD4 T cells compared to checkpoint blockade alone and the efficacy was conditional on granulocytic cells. In addition to myeloid reprogramming in the tumor, ruxolitinib blunts G-CSF signaling in the bone marrow to prevent expression of suppressive and chemotaxis genes in neutrophils. In a clinical trial of Hodgkin lymphoma patients resistant to checkpoint inhibitors, treatment with ruxolitinib significantly reduced neutrophil-to-lymphocyte ratios and levels of suppressive markers in myeloid cells but increased numbers of cytokine-producing T cells. These results support the therapeutic potential of JAK inhibition in combination with checkpoint inhibitors in cancer and highlight the potential of reshaped myeloid immunity to improve immunotherapy. One sentence summary: Ruxolitinib reshapes myeloid immunity to synergize with checkpoint inhibitors

immunology↗