Biology subjects

Ghose, M.

Publications and source records attributed to Ghose, M..

4 recordsLinked to original sources

bioRxiv2026

Tumor reactivity assessment using clonal expression (TRACE) reveals tumor reactive CD8+ T cell heterogeneity across solid tumors

1IntroductionTumor infiltrating lymphocytes (TIL) drive the anti-tumor activity of a broad class of immunotherapies. In situ TIL are composed of T cells that recognize tumor antigens (Tumor Reactive T cells, or TRTs) as well as bystander T cells with specificity for other antigens. TRT clonotypes are associated with a unique and tumor-driven exhausted transcriptional state, enabling single-cell RNA sequencing (scRNA-seq)-based predictive models for TRTs using experimentally validated clone labels. MethodsIn this study, a clonotype-level CD8+ TRT classifier (TRACE) was built using an aggregated dataset of validated tumor reactive clonotypes and associated scRNA-seq data from multiple publications that overcomes the limitations of training on a single dataset, donor, or indication. TRACE does not require dataset manipulation for training or prediction, enabling it to be easily applied to new test datasets as they emerge. ResultsTRACE exhibited robust performance on held-out TIL and PBMC clones - achieving a mean Matthews correlation coefficient of 0.84 and F1-score of 0.85 - comparable to or outperforming other TRT prediction methods. We experimentally confirmed the reactivity of TRACE-identified TRT clones by co-culturing engineered, ex vivo expanded TIL with autologous melanoma tumor cell lines. Finally, we applied TRACE to evaluate the frequency of TRT across hundreds of patient samples from multiple tumor atlases spanning lung, colorectal, and pancreatic cancer. TRACE scores were observed to be significantly higher in exhausted CD8 T cells in tumors but not in exhausted cells in normal adjacent or non-cancer samples, suggesting specificity towards identifying tumor-antigen experienced T cells. ConclusionTRACE is a tumor reactivity scoring algorithm released with open model weights that can be applied to tissue or blood single-cell RNAseq datasets. Its application should be of general interest for characterizing the fraction of TRTs in TIL and for establishing correlations with clinical response to immunotherapies.

immunology↗

bioRxiv2026

Dual-inactivation of Regnase-1 and SOCS1 rewires exhausted CD8+ T cell fate to enhance anti-tumor functionality

The solid tumor microenvironment inhibits the functionality of tumor infiltrating T cells recognizing cognate tumor antigen, driving their differentiation towards terminal exhaustion. Interventions are sought to enhance the anti-tumor functionality of tumor-reactive T cells for clinical benefit. The functional genome regulating CD8+ T cell function against solid tumors was mapped by performing genome-wide, focused, and combination in vivo CRISPR/Cas9 screens using OT1 and PMEL TCR transgenic T cells in B16-OVA, MC38-gp100 and EG7-OVA syngeneic tumor models. The ability of the top single hits and combinations, which include Regnase-1 and SOCS1, to enhance CD8+ T cell anti-tumor function was evaluated in the OT1/B16-OVA model with large and established tumors, the disseminated PMEL/B16F10 tumor model, and in a novel murine TIL syngeneic model. The impact of Regnase-1 and SOCS1 single and dual-inactivation on the differentiation of exhausted CD8+ T cell subsets and on long-term persistent memory following tumor clearance was evaluated in OT1 CD8+ T cells in the B16-OVA model. The impact of single and dual-inactivation of Regnase-1 and SOCS1 on the anti-tumor function of experimental human T cell therapeutics was characterized in CRISPR/Cas9-engineered human TIL derived in vitro and in mesothelin-targeting CAR-Ts in vivo. NF-{kappa}B and cytokine signaling were identified as the top pathways regulating CD8+ T cell anti-tumor function, with Regnase-1 and Suppressor of Cytokine Signaling 1 (SOCS1) the top single and combination edits regulating the accumulation of tumor-specific TCR transgenic CD8+ T cells in syngeneic tumor models. Dual-inactivation of Regnase-1 and SOCS1 cooperated through non-redundant mechanisms to strongly expand intermediate (Texint) and effector (Texeff) exhausted CD8+ T cells within lymphoid tissues and tumor, with CD8+ T cells rewired to display an enhanced effector state and suppressed expression of TOX. Dual-edited persistent T effector memory cells (Tem) were formed following tumor clearance. Lastly, Regnase-1 and SOCS1 inactivation enhanced human Tumor Infiltrating Lymphocyte (TIL) and chimeric antigen receptor T cells (CAR-T) therapy functionality. Collectively, this study systematically mapped pathways regulating CD8+ T cell anti-tumor functionality, with Regnase-1 and SOCS1 dual-inactivation found to maximize anti-tumor function through non-redundant mechanisms.

immunology↗

bioRxiv2023

Elucidating the functional profiles of cultivable bacterial communities in the water and sediments during the southwest monsoon season, along the west coast of India.

Understanding the functional profiles of cultivable bacterial communities is crucial for comprehending their ecological significance in marine environments. This study investigates the functional profiles of cultivable bacterial communities in the water and sediments during the productive, southwest monsoon season, along the west coast of India. The southwest monsoon plays a vital role in shaping the hydrological and biogeochemical characteristics of this region, making it an ideal period to study bacterial communities and their functions. Our study utilizes a cultivation techniques to study taxonomy as well as functional assays to elucidate the diverse organic substrates utilization capabilities of bacterial communities. Cultivable bacteria were isolated from discrete water depths and sediment samples from the coastal and off-shore region. Subsequently the carbohydrase, lipase and protease assays were performed to assess its functional potential. The results of this study reveal a rich diversity of cultivable bacterial communities including, representative from Proteobacteria, Firmicutes and Actinobacterial phylum with diverse functional profiles. The functional analyses provide insights into the metabolic capabilities of the bacteria, including organic substrates degradation, processes. The bacterial taxonomic diversity and enzymes activities were significantly different (p < 0.001) among the water and sediment bacterial morphotypes. In conclusion, this research sheds light on the functional profiles of cultivable bacterial communities in the water and sediments along the west coast of India during the productive southwest monsoon season. The comprehensive analysis of their functional capabilities provides insights into their ecological roles and potential significance in organic matter recycling. These findings contribute to our understanding of microbial diversity and ecosystem functioning in coastal environments and lay the groundwork for further research on harnessing the significance of these bacteria in biogeochemical cycling.

microbiology↗

bioRxiv2023

Influence of seasonal variations in primary productivity on the bacterial community structure at Chlorophyll Maximum (C-Max) depths along the west coast of India.

An increase in primary productivity is recorded annually during the southwest monsoon season along the west coast of India, an important upwelling zone. The influence of the seasonal variations in the in situ primary productivity on the bacterial dynamics and community structure was explored during the non-monsoon and productive monsoon seasons. In the monsoon season, shallower mixed layer depth, increased nutrient concentration and a significant, positive correlation of bacterial carbon (p < 0.01) with primary productivity was observed. Bacterial diversity was assessed in the chlorophyll maxima depths during both seasons based on next-generation, metagenomic analysis. In the non-monsoon season, genera such as Idiomarina, Salinimonas, Marinobacter of Proteobacteria and Bacillus and Lactobacillus of Firmicutes were dominant. These major bacterial genera are shown through canonical correspondence analysis to play an important ecological role. They could be responsible for the increased heterotrophic activity recorded through predicted functional gene profiles in this season. In the monsoon season, increased abundance in the autotrophic Cyanobacteria community and its photosynthetic activity was recorded in the gene profiles. Higher diversity of heterotrophic phyla such as Bacteroidetes, Actinobacteria and a few Candidatus phyla and changes in the diversity of Proteobacteria with a representation of Alteromonas, SAR86 clade and OM60 (NOR5) was observed. These results highlight the bacterial dynamics associated with seasonal variations in primary productivity along the west coast of India.

microbiology↗