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4143 Background: The prognostic role of the gut microbiome, which modulates cancer development and therapeutic response, is unknown in patients with pancreatic ductal adenocarcinoma (PDAC). With increasing utilization of neoadjuvant therapy (NAT) prior to pancreatic cancer surgery, identification of patient-specific biologic signatures associated with NAT response a priori could help inform PDAC precision medicine. Thus, we assessed the influence of the baseline gut microbiome on clinical outcomes in patients with PDAC receiving NAT. Methods: Stool samples were collected at diagnosis from 42 consenting patients with localized PDAC intending to undergo NAT and surgical resection between 2018 and 2020. 16S rRNA sequencing was completed on pre-NAT stool and resected tumor samples. Microbiota alpha diversity and log transformed taxonomic classifications were utilized in multiple regression analyses to predict oncologic outcomes. Results: Five patients progressed during NAT and eight of the 37 operated patients were deemed NAT responders, demonstrating pathologic near complete or partial response (CAP 0-2), T1N0 AJCC 8th staging, and ≥ 80% CA 19-9 reduction. Compared to the gut, the tumor microbiota demonstrated remarkably reduced Shannon diversity (2.4±0.5 vs 1.5±0.4, p< 0.0001) and distinct taxa (75.2±19.7 vs 8.0±4.5, p< 0.0001) and, accordingly, was not associated with clinical outcomes. Overall, several taxa, including Bacteroides and Akkermansia, were enriched in the gut relative to the tumor ( p< 0.001). The gut microbiota of NAT non-responders had an increased proportion of the gemcitabine metabolizing Enterobacteriaceae (additive log ratio (ALR) -3.4±2.0 vs -8.7±0.8, p= 0.0004). NAT responders, by contrast, had an increased proportion of the adaptive immune cell activating Akkermansia (ALR -0.9±1.2 vs -6.2±3.3, p= 0.0004). The incidence of jaundice or biliary stent placement was associated with relative increases in Enterobacteriaceae (+3.3 ALR, p< 0.01 and +4.9 ALR, p< 0.0001) and decreases in Akkermansia (-3.2 ALR, p= 0.02 and -2.4 ALR, p= 0.057), without altering total gut microbiota diversity. Age, sex, BMI, comorbidities, receipt of pre-NAT antibiotics, diagnostic EUS tumor size, resectability, and pre-NAT CA 19-9 were not predictive of NAT response or survival in a univariate regression model. However, inclusion of gut microbiota data improved the ability of the model to predict NAT response ( p= 0.016, adjusted R2 0.76) and survival ( p= 0.001, adjusted R2 0.89), with Enterobacteriaceae (FDR p= 0.012) and Akkermansia (FDR p= 0.015) being significant negative and positive predictors of NAT response, respectively. Conclusions: The baseline gut microbiota could be leveraged as a biomarker of NAT response and prognosis in patients with pancreatic cancer and warrants further investigation.

Tumor immunology has changed the landscape of cancer treatment. Yet, not all patients benefit as cancer immune responsiveness (CIR) remains a limitation in a considerable proportion of cases. The multifactorial determinants of CIR include the genetic makeup of the patient, the genomic instability central to cancer development, the evolutionary emergence of cancer phenotypes under the influence of immune editing, and external modifiers such as demographics, environment, treatment potency, co-morbidities and cancer-independent alterations including immune homeostasis and polymorphisms in the major and minor histocompatibility molecules, cytokines, and chemokines. Based on the premise that cancer is fundamentally a disorder of the genes arising within a cell biologic process, whose deviations from normality determine the rules of engagement with the host’s response, the Society for Immunotherapy of Cancer (SITC) convened a task force of experts from various disciplines including, immunology, oncology, biophysics, structural biology, molecular and cellular biology, genetics, and bioinformatics to address the complexity of CIR from a holistic view. The task force was launched by a workshop held in San Francisco on May 14–15, 2018 aimed at two preeminent goals: 1) to identify the fundamental questions related to CIR and 2) to create an interactive community of experts that could guide scientific and research priorities by forming a logical progression supported by multiple perspectives to uncover mechanisms of CIR. This workshop was a first step toward a second meeting where the focus would be to address the actionability of some of the questions identified by working groups. In this event, five working groups aimed at defining a path to test hypotheses according to their relevance to human cancer and identifying experimental models closest to human biology, which include: 1) Germline-Genetic, 2) Somatic-Genetic and 3) Genomic-Transcriptional contributions to CIR, 4) Determinant(s) of Immunogenic Cell Death that modulate CIR, and 5) Experimental Models that best represent CIR and its conversion to an immune responsive state. This manuscript summarizes the contributions from each group and should be considered as a first milestone in the path toward a more contemporary understanding of CIR. We appreciate that this effort is far from comprehensive and that other relevant aspects related to CIR such as the microbiome, the individual’s recombined T cell and B cell receptors, and the metabolic status of cancer and immune cells were not fully included. These and other important factors will be included in future activities of the taskforce. The taskforce will focus on prioritization and specific actionable approach to answer the identified questions and implementing the collaborations in the follow-up workshop, which will be held in Houston on September 4–5, 2019.