Biology subjects

Cen, P.

Publications and source records attributed to Cen, P..

3 recordsLinked to original sources

bioRxiv2026

Serial Thermal Ablation Induces Abscopal Antitumor Immunity and Reveals Targetable CSF1R-Dependent Resistance in Pancreatic Cancer

Thermal ablation is increasingly used for local control of pancreatic ductal adenocarcinoma (PDAC), but its capacity to induce systemic antitumor immunity and the mechanisms limiting this response remain incompletely defined. Using a bilateral LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx1-Cre (KPC) flank tumor model, we show serial radiofrequency ablation (RFA) enhances local tumor control and induces a robust abscopal response. This effect was associated with increased activation of CD8 T cells and natural killer cells, and was abrogated by CD8 T cell depletion. Single-cell RNA sequencing revealed expansion of cytotoxic immune programs alongside induction of a CSF1R-driven myeloid response consistent with adaptive immune resistance. Although combinatorial blockade of PD-L1 and CD73 augmented systemic antitumor responses, and the addition of CSF1R inhibition in this context further enhanced both local and distant tumor control. These findings identify a CSF1R-dependent myeloid resistance program which constrains ablation-induced systemic immunity and demonstrate that rational combination immunotherapy can potentiate the systemic efficacy of tumor ablation in PDAC. STATEMENT OF TRANSLATIONAL RELEVANCERadiofrequency ablation is a local thermal therapy that induces tumor destruction and modulation of the tumor microenvironment used for treatment of many solid tumors, including pancreatic cancer. Serial thermal ablations induce a CD8+ T cells and NK cell antitumor immunological response; however, Nt5e (CD73) is increased in tumor cells, PD-1 is increased in CD8+ T cells, and serial ablations increase a CSF1R+ macrophage cluster in ablated tumors. Combinational targeting of CD73, PD-L1, and CSF1R alleviates CSF1R-dependent therapeutic resistance and enhances local and systemic tumor control. This study identifies targetable countervailing mechanisms to local ablation therapy and provides a rationale for combinatorial strategies integrating serial tumor ablation with systemic immunomodulatory agents. Future prospective studies should evaluate the influence of timing, dosage, and sequence of ablation on immune priming to improve clinical interventions in pancreatic cancer.

cancer biology↗

bioRxiv2022

Radiofrequency ablation remodels the tumor microenvironment and promotes systemic immunomodulation in pancreatic cancer

Background and AimsPancreatic ductal adenocarcinoma (PDAC) is characterized by resistance to therapy. A major contributing factor to therapeutic failure is profound desmoplasia and a well-documented hypoxic tumor microenvironment (TME). In PDAC, several therapeutic approaches, including chemotherapy and radiation alone or combined with immune checkpoint inhibitors, have shown minimal therapeutic success, placing an imperative need for the discovery and application of innovative treatments. Endoscopic ultrasound guided radiofrequency ablation (EUS-RFA) is a promising immunomodulator therapy for PDAC. In this work, we hypothesized RFA promotes local and systemic stromal and immunomodulating effects that can be identified for new combination therapeutic strategies. MethodsTo test our hypothesis, a syngeneic PDAC mouse model was performed by symmetrically injecting 100k murine KPC cells in bilateral flanks of C57BL/6 female mice. RFA treatment initiated when tumors reached 200-500 mm3 and was performed only in the right flank. The left flank tumor (non-RFA contralateral side) was used as a paired control for further analysis. ResultsRFA promoted a significant reduction in tumor growth rate 4 days after treatment in RFA treated and non-RFA side contralateral tumors from treated mice when compared to controls. Histological analysis revealed a significant increase in expression of cleaved Caspase3 in RFA treated tumors. In addition, collagen deposition and CD31+ cells were significantly elevated in RFA side and non-RFA contralateral tumors from RFA treated mice. Proteome profiling showed changes in C5a and IL-23 in RFA responsive tumors, indicating a role of RFA in modulating intratumoral inflammatory responses. ConclusionsThese data indicate RFA promotes local and systemic anti-tumor responses in a syngeneic mouse model of PDAC implicating RFA treatment for local tumors as well as metastatic disease. Graphical Abstract O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY

cancer biology↗

bioRxiv2020

Decomposing Loss Aversion from Gaze Allocation and Pupil Dilation

Loss-averse decisions, in which one avoids losses at the expense of gains, are highly prevalent. However, the underlying mechanisms remain controversial. The prevailing account highlights a valuation bias that overweighs losses relative to gains, but an alternative view stresses a response bias to avoid choices involving potential losses. Here we couple a computational process model with eye-tracking and pupillometry to develop a physiologicallygrounded framework for the decision process leading to accepting or rejecting gambles with equal odds of winning and losing money. Overall, loss-averse decisions were accompanied by preferential gaze towards losses and increased pupil dilation for accepting gambles. Using our model, we found gaze allocation selectively indexed valuation bias, and pupil dilation selectively indexed response bias. Finally, we demonstrated that our computational model and physiological biomarkers can identify distinct types of loss-averse decision-makers who would otherwise be indistinguishable using conventional approaches. Our study provides an integrative framework for the cognitive processes that drive loss-averse decisions and highlights the biological heterogeneity of loss aversion across individuals. Significance StatementWe revisit the concept of loss aversion by synthesizing distinct views into an integrative framework and by probing physiological biomarkers associated with the behavior. The framework decomposes loss aversion into a valuation bias, which weighs losses over gains, and a response bias, which avoids loss-related choices altogether. Further, we revealed a double dissociation in physiology underlying the decision process. Valuation bias was associated with preferential gaze allocation to losses whereas response bias was associated with pupillary dilation. Our framework exposed biological heterogeneity underlying loss aversion and distinguishes different loss-averse decision makers who are otherwise indistinguishable using conventional approaches. Our integrative approach provides a deeper analysis of the mechanisms underlying loss aversion and incorporates distinct views within a unified biological framework.

neuroscience↗