Biology subjects

Bhandarkar, V.

Publications and source records attributed to Bhandarkar, V..

3 recordsLinked to original sources

bioRxiv2026

Modeling lung adenocarcinoma using layer-by-layer nanoparticles mitigates innate immune cell activation

Lung adenocarcinoma, driven frequently by KRAS and p53 mutations, remains a leading cause of cancer mortality. Current state-of-the-art genetically engineered mouse models often rely on viral delivery of recombinases, such as Cre recombinase, to initiate transformation. However, viral particles can infect and activate innate immune cells, thus potentially impacting studies of tumor-immune dynamics. Here, we develop a layer-by-layer (LbL) polyplex platform using poly({beta}-aminoester) (PBAE) polymers layered with poly-L-aspartic acid (PLD) to deliver Cre mRNA to lungs while avoiding immune cell transfection and activation. PLD-coated nanoparticles (PLD-NPs) exhibit stable mRNA encapsulation and efficient transfection in vitro, even after lyophilization and long-term storage. In KrasLSL-G12D/+;p53flox/flox (KP) mice, PLD-NPs initiate lung adenocarcinomas that mirror human histopathology without infecting or activating dendritic cells and alveolar macrophages, unlike lentiviral (LV) or adenoviral delivery methods. Single-cell transcriptional profiling revealed that LV administration drives long-term upregulation of antigen presentation and costimulatory machinery in lung-resident myeloid populations. This persistent immune activation is avoided by NP delivery. By uncoupling tumor initiation from innate immune activation, this platform enables the high-fidelity interrogation of tumor-immune dynamics, especially for non-inflammation-driven lung cancer.

immunology↗

bioRxiv2026

Lymph node resident memory T cells retain effector capabilities by evading lung resident memory dysfunction.

Resident memory T cells (TRM) mediate localized immunity in barrier tissues while central memory T cells (TCM) recirculate through lymphoid organs to surveil for reinfection. Although TRM are classically associated with peripheral non-lymphoid tissues, they have also been identified within lymph nodes (LNRM) where the mechanisms guiding their formation and functional differences remain poorly understood. Here we used longitudinal antibody labeling to track the migratory history of memory T cells after influenza infection and demonstrate that CD69+CD103+ T cells are resident in the lymph node. LNRM accumulate evenly throughout the lung-draining lymph node and are present within all analyzed LN compartments including, the sub capsular sinus, T cell zone and germinal centers. Epigenetic and transcriptional profiling reveal that LNRM are uniquely poised for cytotoxicity whereas TRM in the lung (LungRM) resemble exhausted cells with elevated expression of inhibitory receptors and increased chromatin accessibility at the Pdcd1 locus. Regulatory network analysis of transcription factors, combined with target gene expression and chromatin accessibility, identified key regulons differentiating TCM, LNRM and LungRM states. Upon antigen re-encounter, LNRM are more proliferative, cytotoxic, and produce more IFN{gamma} compared to LungRM. Notably, we find that LNRM represent the most prevalent subset of memory T cells in human thoracic lymph nodes. These findings highlight functional heterogeneity in TRM and establish LNRM as a distinct and durable memory T cell population bridging features of circulating and tissue-resident cells.

immunology↗

bioRxiv2025

PD-1 blockade during T cell priming enhances long-term protection against metastatic tumors by epigenetically tuning T cell exhaustion

In cancer, CD8+ T cell responses are dominated by exhausted T cells, which can be reinvigorated using immune checkpoint blockade therapy and can control large tumors. However, it remains unclear which T cell fate best supports long-term immunity following tumor regression or clearance and a period of minimal antigen load. This question is particularly relevant following surgical tumor resection, when tuning the immune system could prevent recurrence. To determine which T cell fate provides durable protection following surgery and metastatic rechallenge, we modulated T cell priming using anti-PD-1, IFN-{beta} or agonistic anti-CD40 and assessed effects on CD8+ T cell differentiation and overall survival. IFN-{beta} and anti-CD40 promoted effector and memory-like T cell states, respectively, whereas anti-PD-1 did not markedly alter T cell differentiation, yet conferred the greatest survival benefit against metastatic tumors. Notably, anti-PD-1 induced epigenetic remodeling, which was detectable upon metastatic recall, consistent with the maintenance of a circulatory intermediate-exhausted T cell state. Thus, while effector and memory precursor-like T cells could be generated with IFN-{beta} and agonistic anti-CD40, only the intermediate-exhausted T cell state driven by anti-PD-1 supported durable anti-tumor immunity. SummaryThis study shows that PD-1 blockade during T cell priming promotes a circulatory intermediate-exhausted CD8 T cell state that uniquely supports durable anti-tumor immunity after surgical resection and metastatic challenge, outperforming effector or memory-like T cell responses generated by IFN-{beta} or CD40 agonist treatment, respectively.

immunology↗