Cancer research最新文献

{"title":"Abstract B096: Immune and stromal features of durable complete response to radiation and dual immune checkpoint blockade in pancreatic cancer","authors":"Sarah Kang, Milan Parikh, Leontios Pappas, Lynn Bi, Julie L. Koenig, Beow Y. Yeap, Nicole Carzo, Tarin M. Grillo, Islam Baiev, Olanike Asupoto, Ana Lako, Irena Gushterova, Thomas J. Carmona-LaSalle, Anna L K. Gonye, Emily M. Blaum, Jeffrey W. Clark, Colin D. Weekes, Jill N. Allen, Lawrence S. Blaszkowsky, David P. Ryan, James M. Cleary, Joseph D. Mancias, Benjamin L. Schlechter, Sarah E. Slater, Jennifer Y. Wo Y. Wo, Thomas A. Abrams, Steven M. Corsello, Joseph W. Franses, Marios Giannakis, Jeffrey A. Meyerhardt, Matthew B. Yurgelun, Christine Bolton, Hannah J. Roberts, Sofia von Fedak, Lorraine C. Drapek, Brian M. Wolpin, David T. Ting, Moshe Sade-Feldman, Theodore S. Hong, Nir Hacohen, Aparna Parikh, Arnav Mehta, Ryan J. Park","doi":"10.1158/1538-7445.pancreatic26-b096","DOIUrl":"https://doi.org/10.1158/1538-7445.pancreatic26-b096","url":null,"abstract":"Microsatellite stable (MSS) pancreatic ductal adenocarcinoma (PDAC) is refractory to immune checkpoint blockade, reflecting an immunosuppressive stroma, impaired lymphocyte trafficking, and low neoantigen burden. We conducted a single-arm phase II trial (NCT04361162) combining nivolumab, ipilimumab and radiation therapy to treat patients with pre-treated metastatic MSS PDAC (n=30). While clinical activity was limited overall (3.3% overall response rate, 10% disease control rate, 2.17 months median progression-free survival), one patient achieved a durable complete response (CR) with no evidence of disease after 5 years. To understand the cellular drivers of treatment response, we integrated longitudinal profiling of 33 pre- and on-treatment tumor biopsies from 23 patients, yielding 245,529 single-nucleus and 128,295 single-cell transcriptomes with 27,215 paired single-cell TCR clonotypes, as well as Visium spatial transcriptomics from 13 biopsies, and peripheral blood TCR-sequencing from 25 patients. Across the cohort, treatment was associated with expansion of T, NK, and myeloid cell populations. Lineage tracing of expanded T cell clonotypes revealed a therapy-associated remodeling of pre-existing GZMK+ CD8 clonotypes into CD8 exhausted T cells in the CR patient alone, in contrast to phenotypically stable clones in non-responders. Using a benchmarked tumor-reactivity gene signature (AUROC 0.71–0.95 across validation cohorts), we found predicted tumor-reactive clonotypes were highly concentrated in the CR patient (71% of tumor-reactive cells, 78% of tumor-reactive clonotypes), with peripheral blood TCR-sequencing showing selective expansion of these clonotypes in circulation one year after treatment. The CR patient also uniquely displayed enrichment of interferon-polarized C1Q+ macrophages, an interferon-responsive fibroblast population, and ACKR1+ venous endothelial cells. The CR patient was further characterized by distinct coordination across cell types, reflected in a multicellular interferon hub linking CXCL13+ T cells, CXCL10+ macrophages, and POSTN+FAP+ fibroblasts with increased activity on treatment. Spatial transcriptomics confirmed increased macrophage–T cell co-localization and chemokine signaling (CCL3-CCR1, CXCL9-CXCR3) activity on-treatment, and it additionally nominated ACKR1+ endothelial cells (via CXCL9-ACKR1) as a site of immune cell recruitment. Across independent PDAC cohorts, high ACKR1 expression was associated with improved survival, greater intratumoral TCR richness and clonality, and increased tumor–blood TCR sharing. These findings suggest that productive immunotherapy responses in PDAC require not only tumor-reactive T cells, but also a stromal-vascular niche capable of supporting their recruitment, recirculation and persistence. This may have implications for the design of future immunotherapy and vaccine strategies for PDAC. Citation Format: Sarah Kang, Milan Parikh, Leontios Pappas, Lynn Bi, Julie L. Koenig, Beow Y.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"5 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149048713","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract PR016: High-plex spatial phenotyping resolves immune organization in pancreatic ductal adenocarcinoma","authors":"Deniz G. Olgun, Dennis Gong, Gabriel Francisco Pozo Mattos Pereira, Jingyi Cao, Olivia Kaneko, Peter Wang, Niyati Jhaveri, Yue Hou, Bassem B. Cheikh, HaYeun Ji, Mark Gregory, Jason Reeves, Michael Patrick, Carina Shiau, Jennifer Su, Jimmy A. Guo, Joseph M. Beechem, Huamin Wang, Martin Hemberg, William L. Hwang, Ryan Park","doi":"10.1158/1538-7445.pancreatic26-pr016","DOIUrl":"https://doi.org/10.1158/1538-7445.pancreatic26-pr016","url":null,"abstract":"Pancreatic ductal adenocarcinoma (PDAC) is profoundly immunosuppressive and characteristically exhibits sparse lymphocytic infiltration, yet many tumors harbor focal immune aggregates. The phenotypic diversity and patterns of multicellular organization of these immune aggregates remain incompletely defined. Here, we integrate spatial proteomics and spatial transcriptomics to map PDAC immune aggregates at single-cell resolution and cohort scale. We first optimized high-dimensional immunophenotyping on whole tumor sections using Akoya PhenoCycler-Fusion (CODEX) and performed serial-section integration with Bruker CosMx spatial molecular imaging to relate protein-defined immune and stromal phenotypes to transcriptional programs in nearby malignant glands. Immune aggregates spanned diverse lymphoid and myeloid phenotypes beyond canonical tertiary lymphoid structures and were embedded in distinct malignant and stromal contexts. To determine whether this heterogeneity reflected recurrent patterns of immune-cell organization, we next developed a custom 38-plex panel on Lunaphore COMET and profiled 2,429,896 cells across 264 tumor cores from 147 patients with untreated, resected primary PDAC and linked clinicopathologic data including stage, grade, margin and nodal status, recurrence, and survival. Across this cohort, we characterized immune context at multiple scales by defining multicellular immune communities and developing an interpretable immunoscore that captures coordinated variation in immune composition and spatial architecture. Overall immune infiltration and specific community abundances were associated with clinical outcomes, including a myeloid-rich community with the lowest proportion of T cells near antigen-presenting cells that was associated with worse overall survival. We linked microenvironmental features, including FAP+ fibroblasts, 4HNE-associated oxidative stress, and malignant cell states (classical, basal-like, neural-like progenitor), to variation in multicellular immune communities, their core-level immune ecotypes, and the immunoscore. Further spatial analyses resolved two distinct microenvironments surrounding intratumoral nerves, one characterized by CD163− myeloid cells and the other by fibroblasts and lymphocytes. This study establishes a multiscale framework for resolving immune organization in PDAC and provides a deeply annotated cohort-scale resource for investigating tumor–immune–stroma interactions. ChatGPT was used to proofread and refine the wording of this abstract; all text was reviewed and edited by the authors. Citation Format: Deniz G. Olgun, Dennis Gong, Gabriel Francisco Pozo Mattos Pereira, Jingyi Cao, Olivia Kaneko, Peter Wang, Niyati Jhaveri, Yue Hou, Bassem B. Cheikh, HaYeun Ji, Mark Gregory, Jason Reeves, Michael Patrick, Carina Shiau, Jennifer Su, Jimmy A. Guo, Joseph M. Beechem, Huamin Wang, Martin Hemberg, William L. Hwang, Ryan Park. High-plex spatial phenotyping resolves immune organization in pancre","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"52 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149048721","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract A063: Lipid metabolism-driven remodeling of immune ecosystem promotes pancreatic cancer progression and metastasis","authors":"Bo Tu, Bo Tu","doi":"10.1158/1538-7445.pancreatic26-a063","DOIUrl":"https://doi.org/10.1158/1538-7445.pancreatic26-a063","url":null,"abstract":"Pancreatic ductal adenocarcinoma (PDAC) is a devastating malignancy characterized by aggressive metastatic progression, profound immunosuppression, and limited therapeutic options. Increasing evidence suggests that metabolic reprogramming extends beyond fuel provision and actively reshapes the tumor microenvironment (TME) to promote immune evasion and metastatic dissemination. However, the molecular mechanisms linking lipid metabolism to oncogenic signaling and remodeling of immune ecosystem remain poorly understood. Our preliminary studies identify Fatty Acid Synthase (FASN) as a non-canonical signaling hub that orchestrates immune exclusion and metastatic progression in PDAC. We uncovered a novel biochemical pathway in which FASN promotes site-specific palmitoylation of Myc, thereby enhancing c-Myc oncogenic activity. This signaling axis sustains oncogenic transcriptional programs, recruits immunosuppressive myeloid populations, and promotes CD8+ T-cell dysfunction, ultimately establishing a permissive metastatic niche. To translate these findings into therapeutic opportunities, we investigated the molecular mechanisms regulating c-Myc palmitoylation in PDAC and determined how palmitoyl transferase (ZDHHC) mediated palmitoylation controls oncogenic signaling. Using multiplex immunofluorescence (mIF), we mapped the spatial immune ecosystem of metastatic PDAC and characterized interactions between FASN-high tumor cells, macrophage populations, and dysfunctional CD8+ T cells within metastatic niches. Furthermore, leveraging our unique KPFFC (FASN conditional knockout) mouse model together with the clinical-stage FASN inhibitor, denifanstat, we evaluated whether disrupting the FASN–ZDHHC–c-Myc signaling axis can remodel the TME, restore antitumor immunity, and enhance sensitivity to immune checkpoint blockade. By shifting the focus of FASN biology from metabolic fuel production to its functional oncogenic signaling architecture, this study uncovers a therapeutically actionable immunometabolic vulnerability and establishes a mechanistic foundation for precision-guided immunometabolic therapies in pancreatic cancer. Citation Format: Bo Tu, Bo Tu. Lipid metabolism-driven remodeling of immune ecosystem promotes pancreatic cancer progression and metastasis [abstract]. In: Proceedings of the AACR Conference on Pancreatic Cancer: New Frontiers in Biology and Therapeutic Development; 2026 Sep 25-28; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(18_Suppl_2): nr A063.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"1 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149048754","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract A106: Virtual Stromal Staining of Routine Histology as an Exploratory, Stroma-Aware Prognostic Readout in Pancreatic Cancer","authors":"Megan Rothney, David Sriker, Yair Rivenson","doi":"10.1158/1538-7445.pancreatic26-a106","DOIUrl":"https://doi.org/10.1158/1538-7445.pancreatic26-a106","url":null,"abstract":"Introduction. Pancreatic ductal adenocarcinoma (PDAC) is defined by a dense desmoplastic stroma central to its biology, yet clinical staging discriminates survival weakly. For over a decade the stroma was pursued as a therapeutic target; yet stroma-directed strategies, have shown mixed results. These challenges recast the stroma as heterogeneous, both tumor-restraining and tumor-promoting, and exposed a gap: no reliable way to read prognostic stromal signals from routine material. We asked whether stromal information in H&E whole-slide images, made explicit by virtual staining, could serve as an interpretable prognostic readout. Methods. From each digitized H&E whole-slide image we generated virtual stains spanning stromal (trichrome), epithelial (pan-cytokeratin), immune (CD45), and molecular (p53) compartments. Each virtual stain was synthesized from the H&E at the same spatial coordinates, producing a pixel-aligned representation of stromal, epithelial, immune, or molecular-associated morphology without additional tissue sections or chemical staining. Tiles were encoded with a pathology foundation model adapted per stain, with auxiliary molecular supervision, and aggregated into patient-level risk by cross-attention multiple-instance learning under a Cox objective. Treating H&E as one channel among the virtual stains, we compared stain subsets and evaluated image-derived risk against clinical variables on prespecified endpoints, using patient-level 5-fold cross-validation and a 15-seed ensemble in TCGA-PAAD (181 patients; 99 OSS and 79 DSS events). Results. Adding the virtual stromal (trichrome) channel to H&E produced the best discrimination (out-of-fold C-index 0.674; H&E alone ∼0.63); the stromal channel, rather than the epithelial, immune, or molecular channels, provided the strongest incremental value, consistent with stroma as PDAC's dominant prognostic compartment. Image-derived risk exceeded clinical staging (0.673 vs 0.565) and provided largely complementary information. Image-only performance was at or above published TCGA-PAAD benchmarks (staging ∼0.60; H&E-only ∼0.58–0.62; histology-plus-genomics 0.653) without sequencing. A median risk split separated OSS and DSS (OS hazard ratio 2.42, log-rank p=1.6×10−5; DSS 2.34), with signal strongest in resectable subgroups (node-negative OS C-index ∼0.76; T1–2 OS C-index ∼0.77). Conclusions. In this exploratory single-cohort retrospective analysis, a virtual stromal stain from routine H&E behaved as an interpretable, stroma-aware prognostic readout, adding information beyond clinical staging and reaching multimodal-range discrimination without sequencing, raising the hypothesis that virtual staining surfaces molecular-associated signal latent in H&E. Findings are prognostic associations, not treatment benefit, from one public cohort with normal-tissue admixture, and require external validation with tumor-region curation. If validated, it could provide the ","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"13 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149048822","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract B012: Pan-RAS Inhibition Reprograms T Cell Immunity within the Pancreatic Adaptive Immune Microenvironment","authors":"Rashmi J. Kumar, Emily Lasse-Opsahl, Lauren Gerbereux, Carlos E. Espinoza, Jiayue Wang, Jude Ogechukwu Okoye, Timothy L. Frankel, Marina Pasca di Magliano","doi":"10.1158/1538-7445.pancreatic26-b012","DOIUrl":"https://doi.org/10.1158/1538-7445.pancreatic26-b012","url":null,"abstract":"Introduction: The advent of pan-RAS and allele-specific inhibitors in clinical trials have created an urgent need to understand how RAS inhibition remodels the pancreatic immune microenvironment and alters anti-tumor immunity, to guide rational combinations with immunotherapy. Methods: We used a murine model with pancreas-specific, doxycycline-inducible, reversible oncogenic KRAS G12D expression to compare three states: the RAS-ON, RAS-OFF (KRAS G12D-specific genetic inactivation), and the RAS-inhibited (RAS-i) states. RAS-i condition is defined by treatment with the preclinical pan-RAS(ON) inhibitor RMC-7977 (Note: as this is an investigational compound there is no generic drug name). Single-cell sequencing and transcriptomic profiling were used to evaluate immune remodeling in the pancreas. Changes in immune phenotypes discovered through transcriptomic profiling were validated using a custom 25-marker spectral flow cytometry panel in an orthotopic inducible-KRAS G12D pancreatic adenocarcinoma model. Results: Single cell sequencing showed expansion of the T cell compartment after RAS inactivation (RAS-OFF) or inhibition (RAS-i) compared with the RAS-ON pancreas, driven primarily by CD8+ T cells. However, CD8+ T cells exhibit distinct transcriptomic changes between RAS-OFF and RAS-i states. Pan-RAS inhibition increased recruitment of naive T cells into the pancreatic microenvironment but was associated with limited differentiation into cytotoxic effector CD8+ T cells capable of expressing Prf1, Gzmb, and Ifng in the RAS-i cohort. In contrast, the RAS-OFF state promoted robust effector differentiation, including early and late effector populations with upregulation of Fasl, expansion of central memory T cells, and reduced naive T cell abundance. Differential gene analysis shows increased expression of Il7r expression in RAS-OFF versus RAS-i T cells, consistent with enhanced self-renewal and clonal expansion capacity. Orthogonal validation with spectral flow cytometry confirmed these transcriptomic findings: the RAS-OFF state contained a higher proportion of CD3+CD8+CD62LLowCD44High effector T cells compared to RAS-i. Consistently, a significant fraction of CD8+ T cells in the RAS-i cohort remained CD62LHigh naive T cells. Moreover, orthotopic tumor burden was highest in RAS-ON, lowest in RAS-OFF tumors, with an intermediate burden after RAS-i. Conclusion: Taken together, pan-RAS inhibition remodels the pancreatic immune microenvironment resulting in diminished CD8+ T cell effector abundance and functionality, as a potential consequence of systemic pan-RAS inhibition. Comparatively, RAS-OFF, with KRAS G12D allele-specific inactivation, shows increased T cell recruitment, early activation and successful conversion to effector T cells. These observations suggest that the immunologic consequences of systemic pan-RAS inhibition should be considered when designing RAS inhibitor-immunotherapy combinatorial therapies for pancreatic cancer. Citation Format","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"22 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149048823","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract PR014: Integrated translational analyses of the first generation KRAS G12D degrader setidegrasib identify mechanisms of response and resistance and offers rational combination strategies in pancreatic cancer","authors":"Wungki Park, Shilpa Kadam, Anup Kasi, Teresa Macarulla, Christos Fountzilas, Makoto Ueno, Takeshi Saito, Stanley C. Gill, Erica Tong, Hui Yang, Sebastian Gloskowski, Joshua Sallin, Gustave Ronteix, Fanny Jaulin, Hisaki Fujii","doi":"10.1158/1538-7445.pancreatic26-pr014","DOIUrl":"https://doi.org/10.1158/1538-7445.pancreatic26-pr014","url":null,"abstract":"Background: KRAS G12D is a prevalent oncogenic driver in PDAC, which has a high unmet need due to few effective targeted therapies. Setidegrasib, a novel KRAS G12D-targeted protein degrader, eliminates the oncogenic driver to suppress downstream signaling and induce tumor cell death. Early clinical activity was reported in an ongoing Phase 1 study (NCT05382559). We present exploratory analyses to characterize the biological activity of setidegrasib and inform biomarker-driven combination strategies. Methods: Patients with locally advanced KRAS G12D-mutant PDAC and prior standard therapies received 140–800 mg setidegrasib monotherapy IV QW. Longitudinal tumor biopsies and plasma were analyzed by transcriptomic profiling to assess KRAS-MAPK signaling, tumor cell states, and the tumor microenvironment (TME). ctDNA analyses enabled real-time monitoring of tumor burden and molecular response. Target engagement was assessed by KRAS G12D IHC, downstream pharmacodynamic effects by tumor gene expression profiling, and TME by multiplex immunofluorescence. Parallel patient-derived organoid (PDO) studies and AI modeling evaluated resistance mechanisms and combination strategies. Results: Data cutoff was November 10, 2025. Samples from 124 patients with KRAS G12D-mutant PDAC (10–90mg=26; 140mg=5; 200mg=12; 300mg=30; 450mg=10; 600mg=31; 800mg=10) were analyzed. Setidegrasib demonstrated durable on-target activity, including robust KRAS G12D degradation (median 95.5%) and downstream MAPK suppression. Transcriptomic and proteomic analyses confirmed differential inhibition of MYC, RAS, and cell-cycle signaling in responders versus non-responders. Baseline tumors from non-responders harbored more co-mutations than responders (NR:R; TP53, 93:87%; SMAD4, 29:0%; CDKN2A, 50:20%; MTAP, 21:0%; EGFR, 7:0%). Major molecular responses were observed in 90% (9/10) of responders by C2D1, marked by a >90% reduction in KRAS G12D ctDNA VAF. Distinct ctDNA trajectories of response and resistance were observed. Progressors exhibited epithelial-mesenchymal transition programs, indicating adaptive tumor plasticity and resistance evolution. Responders demonstrated host anti-tumor immune activation characterized by apoptotic tumor cell death, GZMB+ CD8+ T-cell-mediated tumor clearance through Fas/FasL interactions, and IFN-γ signaling, followed by immune exhaustion with increased PD-L1 expression. PDO studies and AI modeling predicted clinical outcomes and biological activity, and further demonstrated improved outcomes with setidegrasib plus FOLFIRINOX, supporting a rational combination strategy. Conclusions: Setidegrasib demonstrated promising activity in PDAC with robust target engagement, durable pathway suppression, and TME modulation. Translational analyses identified a distinct, targetable resistance landscape, supporting continued development of setidegrasib in combination with FOLFIRINOX for PDAC (NCT07409272) to enhance clinical benefit. Citation Format: Wungki Park, S","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"22 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149048719","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract B108: CXCR4 inhibition reprograms immune checkpoint networks and enhances anti-tumor immunity in patient-derived pancreatic cancer organoid–PBMC co-cultures","authors":"ILENIA PELLICCIOTTA, Gulam Manji, Alex Raufi, Emily Alouani","doi":"10.1158/1538-7445.pancreatic26-b108","DOIUrl":"https://doi.org/10.1158/1538-7445.pancreatic26-b108","url":null,"abstract":"Background: Pancreatic ductal adenocarcinoma (PDAC) remains largely refractory to immunotherapy because of its immunosuppressive, T-cell–excluded microenvironment. Immune checkpoint blockade, alone or with chemotherapy, has shown limited efficacy, likely due to redundant suppressive pathways. CAF-derived CXCL12 acting through CXCR4 is a key mediator of immune exclusion. We recently demonstrated a 65% response rate in a small phase II trial combining gemcitabine-based chemotherapy, CXCR4 inhibition, and PD-1 blockade. To build on this activity, we developed a patient-specific ex vivo organoid model to define CXCL12/CXCR4-mediated immune regulation and identify additional cellular and molecular targets to enhance antitumor efficacy. Methods: Patient-derived tumor organoids (PDTOs) were established from surgical resections of treatment-naïve patients with pancreatic cancer and co-cultured with matched peripheral blood mononuclear cells (PBMCs). PBMC migration toward PDTOs was assessed in a three-dimensional co-culture system. Immune-cell activation and infiltration and tumor-cell apoptosis were evaluated by flow cytometry and immunofluorescence. The effects of the CXCR4 antagonist AMD3100 on immune checkpoint receptor expression in PBMCs and corresponding ligand expression in PDTOs were assessed alone and with immune checkpoint blockade. Results: Co-culture of PDAC patient–derived PBMCs with MiaPaCa-2 and PANC-1 cells and with allogeneic and autologous PDTOs reduced tumor cell numbers in the range of 3.5 to 4.9-fold. In contrast, PBMCs from healthy donors produced minimal tumor-cell killing. Relative to PBMC monoculture, patient-derived co-cultures increased activated CD69+ immune cells, including CD8+ T cells and CD56+ NK cells, with variable CD4+ T-cell activation; no lymphocyte activation was observed with healthy-donor PBMCs. AMD3100 pretreatment enhanced CD8+ T-cell migration toward autologous PDTOs in Matrigel and, following infiltration, increased PBMC proliferation and the abundance of activated T and NK cells expressing IFNγ, CD69, and granzyme B. CXCR4 inhibition also modulated PD-1, TIGIT, NKG2A, LAG-3, and TIM-3 expression in a patient-specific manner. PDAC-derived organoids expressed multiple immune-regulatory molecules, including PD-L1, TIGIT-L, HLA-E, CD73, FasL, IL-10, CXCL12, and calreticulin, indicating both checkpoint-dependent and soluble immune regulation. AMD3100 similarly altered checkpoint expression in PDTOs. Combined treatment of PBMCs and PDTOs with AMD3100 and PD-1 blockade further enhanced T-cell migration and activation and increased PDTO apoptosis, supporting the activity of this combination. Conclusions: Patient-specific PDTO–PBMC models demonstrate that CXCR4 inhibition enhances immune-cell infiltration and activation, modulates checkpoint expression, and promotes tumor-cell killing, supporting combined CXCR4 and PD-1 blockade. A randomized phase II trial evaluating this strategy with gemcitabine and nab-paclitaxel i","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"13 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149048608","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract B081: Tumor-associated antigen-specific immune profiling reveals distinct immunological responses to chemotherapy in pancreatic ductal adenocarcinoma","authors":"Silvia Brugiapaglia, Erika Ostorero, Bruno Castellino, Rosella Spadi, Francesco Novelli","doi":"10.1158/1538-7445.pancreatic26-b081","DOIUrl":"https://doi.org/10.1158/1538-7445.pancreatic26-b081","url":null,"abstract":"Background: Pancreatic ductal adenocarcinoma (PDAC) is characterized by profound immunosuppression and limited responsiveness to immunotherapy. We hypothesized that integrating functional antigen-specific immune responses with clinical parameters could identify patients more likely to benefit from antigen-directed immunotherapies. Methods: Peripheral blood mononuclear cells (PBMCs) and serum samples were collected from PDAC patients before and after treatment with Gemcitabine/nab-paclitaxel (GemNab) or FOLFIRINOX. Humoral immunity was assessed by measuring antibodies against a panel of tumor-associated antigens (TAAs). PBMCs were stimulated in vitro with the same antigen panel, and antigen-specific responses were evaluated by lymphocyte proliferation together with IFN-γ and IL-10 secretion. These immune parameters were integrated into a composite immune suitability score, which was further combined with clinically relevant variables, including overall survival, CA19-9, CEA, performance status, and metastatic burden, to define patient-specific immune profiles and evaluate their potential suitability for antigen-directed immunotherapy. Results: Chemotherapy differentially remodeled antigen-specific immunity. Compared with FOLFIRINOX, GemNab was associated with a more consistent enhancement of TAA-specific immune responses, characterized by increased proliferative capacity and a predominance of IFN-γ over IL-10 production. Considerable interpatient heterogeneity was observed in both humoral and cellular immune responses. Integration of immune and clinical variables generated distinct immune suitability profiles that stratified patients according to the strength of their antigen-specific immunity and clinical outcome. Patients with higher composite immune suitability scores displayed more favorable clinical characteristics and mounted stronger post-treatment antigen-specific responses, identifying a subgroup with increased immunotherapeutic potential. Conclusions: Integrative profiling of antigen-specific humoral and cellular immunity, combined with clinical parameters, enables the identification of distinct immune suitability profiles in PDAC. This approach provides a framework for patient stratification and reveals an immunotherapeutic window in which antigen-targeted vaccination and other antigen-specific immunotherapies may be most effective. Citation Format: Silvia Brugiapaglia, Erika Ostorero, Bruno Castellino, Rosella Spadi, Francesco Novelli. Tumor-associated antigen-specific immune profiling reveals distinct immunological responses to chemotherapy in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Conference on Pancreatic Cancer: New Frontiers in Biology and Therapeutic Development; 2026 Sep 25-28; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(18_Suppl_2): nr B081.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"30 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149048616","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract B055: Combinatorial drug screening identifies synergistic combinations that sensitize resistant PDAC cells to cuproptosis-inducer NSC 319726","authors":"Janine Kaupe, Christian Schneeweis, Dieter Saur","doi":"10.1158/1538-7445.pancreatic26-b055","DOIUrl":"https://doi.org/10.1158/1538-7445.pancreatic26-b055","url":null,"abstract":"Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignancies and is characterized by profound therapeutic resistance and poor clinical outcome. Due to the limited efficacy of monotherapies, combination strategies represent a promising approach to simultaneously target multiple signaling pathways and overcome resistance mechanisms. NSC 319726 (ZMC1) was initially described as a mutant p53 reactivator, but emerging evidence indicates that its cytotoxicity is primarily mediated by copper-dependent mechanisms. Acting as a copper ionophore, NSC 319726 induces cuproptosis, a recently discovered regulated cell death mechanism characterized by excess intracellular copper accumulation, leading to lipoylated mitochondrial protein aggregation and loss of Fe-S cluster proteins, ultimately triggering proteotoxic stress and cell death. The aim of this study was to identify synergistic drug combinations that sensitize NSC 319726-resistant PDAC cells to cuproptosis. Therefore, a panel of 5 murine PDAC cell lines spanning a range of NSC 319726 sensitivity was screened with NSC 319726 as an anchor drug at a fixed concentration in combination with 95 compounds from a curated drug library. The most promising candidates were prioritized based on ΔAUC (delta area-under-the-curve) values and 5 top hits subsequently validated in multi-dose combinatorial matrices using long-term clonogenic assays. Drug interactions were quantified using ZIP synergy score models. Several combinations exhibited pronounced synergistic effects, effectively sensitizing previously resistant PDAC cell lines to NSC 319726. Notably, the identified hits predominantly targeted different metabolic pathways such as glycolysis, mitochondrial metabolism and redox homeostasis. Importantly, synergistic interactions were largely restricted to resistant cell lines, with little to no synergy observed in sensitive lines, suggesting a selectivity window that may be therapeutically exploitable. These findings suggest that rational combination strategies can significantly enhance the antitumor activity of NSC 319726 and identify key targets for further mechanistic and in vivo validation. Citation Format: Janine Kaupe, Christian Schneeweis, Dieter Saur. Combinatorial drug screening identifies synergistic combinations that sensitize resistant PDAC cells to cuproptosis-inducer NSC 319726 [abstract]. In: Proceedings of the AACR Conference on Pancreatic Cancer: New Frontiers in Biology and Therapeutic Development; 2026 Sep 25-28; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(18_Suppl_2): nr B055.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"396 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149048638","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract B059: Loss of Cullin-RING Ligase 5 mediates resistance to RAS inhibition in pancreatic cancer","authors":"Cassandra S. Markham, Ilze M. Olivi Gomes, Yi Di, Wenxue Li, Molly Schiffer, Yansheng Liu, Mandar D. Muzumdar","doi":"10.1158/1538-7445.pancreatic26-b059","DOIUrl":"https://doi.org/10.1158/1538-7445.pancreatic26-b059","url":null,"abstract":"The proto-oncogene KRAS is mutated in greater than 90% of pancreatic ductal adenocarcinoma (PDAC). Although newly developed multi-RAS(ON) inhibitors (daraxonrasib) have significantly improved progression-free and overall survival compared with current standard-of-care chemotherapy in PDAC patients, both clinical and preclinical studies demonstrate that resistance inevitably emerges. Non-genetic (adaptive) resistance to RAS-targeted therapies accounts for up to 50% of cases of clinical resistance, but the underlying mechanisms remain incompletely understood. Proteostasis, in part mediated by the ubiquitin-proteasome system (UPS), a modular network of ubiquitin ligases that selectively targets proteins for degradation by the 26S proteasome, is essential for cancer cell survival during RAS pathway inhibition. We hypothesized that, because the UPS is modular, selective disruption of individual UPS components or complexes stabilizes specific proteins that promote growth or survival following RAS inhibition, thereby driving resistance without globally impairing proteostasis. Consistent with this hypothesis, genome-wide and UPS-focused pooled CRISPR screens, followed by validation using fluorescence competition and colony-forming assays, converged on loss of multiple components of the CRL5 (Cullin-RING ligase 5) complex—including CUL5, UBE2F, and ARIH2—as promoting selective outgrowth of PDAC models subjected to either genetic (CRISPR-mediated KRAS knockout) or pharmacologic RAS inhibition (daraxonrasib). Mechanistically, CRL5-deficient cells exhibited reduced G1 arrest without significant differences in apoptosis or senescence with chronic RAS inhibition, indicating that the observed growth advantage is driven by altered cell-cycle regulation rather than apoptotic escape. Consistent with the role of CRL5 in post-translational regulation, transcriptional profiling revealed nearly identical gene expression programs in CRL5-intact and CRL5-deficient PDAC cells, with no differentially expressed genes or enriched pathways under either basal conditions or following prolonged RAS inhibition. Likewise, pathway-level biochemical and transcriptional analyses detected no evidence of sustained rewiring of the canonical survival pathways examined following chronic RAS inhibition in CRL5-deficient cells, including MAPK, mTOR, YAP, NF-κB, and JAK/STAT signaling. Together, these findings suggest that CRL5-mediated resistance is driven by altered protein stability rather than transcriptional or signaling rewiring. Ongoing studies seek to evaluate the contribution of CRL5 loss to RAS inhibitor resistance in vivo and to identify CRL5 substrates responsible for diminished G1 arrest using integrated steady-state proteomic and phosphoproteomic analyses. Collectively, these findings and ongoing studies define how selective modulation of protein degradation governs adaptive resistance to RAS inhibition and provide a framework for developing rational combination strategies to ","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"70 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149048641","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}