Leukocyte Heterogeneity in Pancreatic Ductal Adenocarcinoma: Phenotypic and Spatial Features Associated with Clinical Outcome

Abstract

Immunotherapies targeting aspects of T cell functionality are efficacious in many solid tumors, but pancreatic ductal adenocarcinoma (PDAC) remains refractory to these treatments. Deeper understanding of the PDAC immune ecosystem is needed to identify additional therapeutic targets and predictive biomarkers for therapeutic response and resistance monitoring. To address these needs, we quantitatively evaluated leukocyte contexture in 135 human PDACs at single-cell resolution by profiling density and spatial distribution of myeloid and lymphoid cells within histopathologically defined regions of surgical resections from treatment-naive and presurgically (neoadjuvant)–treated patients and biopsy specimens from metastatic PDAC. Resultant data establish an immune atlas of PDAC heterogeneity, identify leukocyte features correlating with clinical outcomes, and, through an in silico study, provide guidance for use of PDAC tissue microarrays to optimally measure intratumoral immune heterogeneity. Atlas data have direct applicability as a reference for evaluating immune responses to investigational neoadjuvant PDAC therapeutics where pretherapy baseline specimens are not available. Significance: We provide a phenotypic and spatial immune atlas of human PDAC identifying leukocyte composition at steady state and following standard neoadjuvant therapies. These data have broad utility as a resource that can inform on leukocyte responses to emerging therapies where baseline tissues were not acquired. This article is highlighted in the In This Issue feature, p. 1861

Applications of single-cell sequencing in cancer research: progress and perspectives

“…By integrating clinical pathological information and single-cell sequencing data, novel diagnostic and prognostic biomarkers and potential therapeutically relevant cell types or states could be deciphered [ 70 ]. In conclusion, The Cancer Cell Atlas can provide reference information for neoadjuvant therapy, especially for those for which baseline guidance is lacking [ 71 ].…”

Therapeutic Potential of Targeting Stromal Crosstalk-Mediated Immune Suppression in Pancreatic Cancer

“…The advent of next-generation sequencing technology and largescale tumor molecular profiling has shed light on the heterogeneous immune infiltration and tumor microenvironment in human PDA both across and within tumors and the heterogeneity in the expression levels of checkpoints on tumor infiltrating T cells (11,(148)(149)(150). Based on these considerations, it is important to understand the variety and individual differences in immune response for future translational studies and clinical trials, including personalized immunotherapy approaches.…”

Neoadjuvant Selicrelumab, an Agonist CD40 Antibody, Induces Changes in the Tumor Microenvironment in Patients with Resectable Pancreatic Cancer

“…Surgical resection specimens from contemporary treatment-na€ ve patients or patients treated with neoadjuvant chemotherapy/chemoradiotherapy were obtained with site IRB approval and written informed consent from the patients at the University of Pennsylvania, Dana-Farber Cancer Institute/Brigham and Women's Hospital, and the Oregon Health and Science University (12). Peripheral blood from normal donors was obtained after written informed consent with University of Pennsylvania IRB approval.…”

“…Here, we performed a clinical trial of the CD40 mAb selicrelumab (10,11) with or without chemotherapy given in both the neoadjuvant and adjuvant settings for patients with resectable PDAC. Application of a curated antibody panel by multiplexed IHC (mIHC) on resection samples revealed major alterations in the TME of patients receiving selicrelumab compared with samples from therapy-na€ ve control PDAC patients (12). Marked T-cell infiltration in the TME after selicrelumab was associated with loss of stroma, systemic inflammation, and T-cell activation.…”