Biology subjects

Harwood, J.

Publications and source records attributed to Harwood, J..

4 recordsLinked to original sources

bioRxiv2026

A CAR T cell-amplified suppressive B cell circuit in AML

Immunotherapy in acute myeloid leukemia (AML) is constrained by a hostile bone marrow niche. Here we identify atypical memory B cells (Batyp) as a suppressive population within this microenvironment. Across single cell and flow cytometry cohorts, Batyp were expanded in AML, and their molecular and phenotypic profiles resembled those of atypical B cells associated with chronic inflammatory conditions. Batyp were polarized within the AML microenvironment, and this was amplified by CAR T cell-AML interactions. Mechanistically, polarization was dependent on Toll-like receptor, interferon and CD70-CD27 signaling. Batyp suppressed T cell and CAR T cell responses via PD-1- and TGF-beta signaling, and were enriched in non-responding patients with AML and myeloma. CD180-directed CAR T cells, targeting an antigen shared by Batyp and AML blasts, resisted suppression in vitro and cleared disease in B cell-humanized xenografts while sparing hematopoietic stem cells, with B cell engagement further enhancing their expansion. CAR T cells thus reinforce their own suppressive niche through Batyp polarization, a constraint that can be relieved by dual blast- and B cell-targeting strategies.

immunology↗

bioRxiv2026

B cells sustain tumor-specific CD4 T cells to promote response to PD-1 targeted therapy

Immunotherapy transformed cancer treatment, yet precise correlates of response remain to be defined. While intratumoral follicular helper like (Tfhl) CD4 T cells and IgG1+ B cells have been associated with improved outcomes to PD-1 blockade for hepatocellular carcinoma (HCC), their mechanisms contributing to response are unclear. To address this question, we developed a murine model of HCC and examined CD8, CD4 and B cell responses. Increasing CD4-help sensitizes mice to PD-1 blockade, in a CD4- and CD8-dependent manner. Tumor-specific CD4 T cells contained Tfhl and Th1 populations, and both Bcl6 and T-bet were required for efficacy. Antigen-specific B cells were essential for CD4-helper expansion, yet secretion of antibodies was not required for long-term survival. Thus, B cells are critical for effective immunotherapy, but secreted antibodies are not.

immunology↗

bioRxiv2026

A kinome inhibitor screen implicates adhesion and growth factor signaling in cellular recovery after caspase activation

Apoptosis is a common form of regulated cell death and requires cysteine-aspartic proteases called effector caspases. Caspase activation triggers positive feedback, leading to the idea that apoptosis is irreversible. However, we and others have demonstrated that cancer cells can survive effector caspase activation and become more aggressive and drug-resistant as a result. Despite the profound implications of apoptotic reversal, also known as anastasis, for both regenerative medicine and cancer therapy, the molecular pathways that enable cells to survive executioner caspase activation remain largely unmapped. To systematically dissect this phenomenon, we developed a quantitative screening platform that combines inducible caspase activation with kinome-wide pharmacological profiling. This approach uniquely allowed us to: (1) identify pharmacological modulators of post-caspase survival, (2) identify specific kinases regulating post-caspase survival, and (3) distinguish general toxicity from anastasis effects. This approach implicated regulators of cell adhesion and the cytoskeleton, consistent with the known rounding of apoptotic cells and respreading during recovery. Growth factor signaling also emerged from the analysis. In addition to its expected effects on unstressed cells, fetal bovine serum markedly increased anastasis. Some growth factor combinations were more effective than individual ones at recapitulating the serum effect. Similarly, pleiotropic kinase inhibitors were generally more effective than selective ones. Nevertheless, selective Rho kinase inhibition significantly enhanced anastasis whereas Akt inhibition impaired it, suggesting that these kinases serve as central nodes that integrate multiple upstream inputs. Beyond identifying specific kinase targets, our work provides a framework for anti-anastasis therapies that could prevent cancer cell recovery after chemotherapy.

cell biology↗

bioRxiv2018

Gene-Based Analysis in HRC Imputed Genome Wide Association Data Identifies Three Novel Genes For Alzheimer’s Disease

A novel POLARIS gene-based analysis approach was employed to compute gene-based polygenic risk score (PRS) for all individuals in the latest HRC imputed GERAD (N cases=3,332 and N controls=9,832) data using the International Genomics of Alzheimers Project summary statistics (N cases=13,676 and N controls=27,322, excluding GERAD subjects) to identify the SNPs and weight their risk alleles for the PRS score. SNPs were assigned to known, protein coding genes using GENCODE (v19). SNPs are assigned using both 1) no window around the gene and 2) a window of 35kb upstream and 10kb downstream to include transcriptional regulatory elements. The overall association of a gene is determined using a logistic regression model, adjusting for population covariates.\n\nThree novel gene-wide significant genes were determined from the POLARIS gene-based analysis using a gene window; PPARGC1A, RORA and ZNF423. The ZNF423 gene resides in an Alzheimers disease (AD)-specific protein network which also includes other AD-related genes. The PPARGC1A gene has been linked to energy metabolism and the generation of amyloid beta plaques and the RORA has strong links with genes which are differentially expressed in the hippocampus. We also demonstrate no enrichment for genes in either loss of function intolerant or conserved noncoding sequence regions.

genetics↗