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Background Pancreatic Ductal Adenocarcinoma (PDAC) is an aggressive cancer and closely associated with cachexia. Characterized by irreversible wasting of skeletal muscles with or without fat loss and systemic inflammation, cachexia reduces the efficacy of various anti-cancer interventions and enhances the morbidity of PDAC. Recent research suggests that cachexia confers resistance to immune-checkpoint inhibition in several cancers, indicating an intricate crosstalk with immunological pathways. The bidirectional relationship between cachexia and the immune system in PDAC is poorly understood, necessitating the development of novel preclinical models.Methods The SIYRYYGL (SIY) antigen-expressing PK5L1948 tumor cells, derived from KPC-LSIY mice ( Kras LSL-G12D/ + Tp53LSL-R172H/ + Pdx1-Cre/R26LSL-LSIY), were orthotopically injected into the pancreas of male and female C57BL/6J mice and hallmarks of cachexia were assessed after 21 days. Tumor weight, terminal tumor-adjusted body weight, skeletal muscle, adipose tissue, liver and spleen masses, expression of proteolytic markers and grip strength were recorded to validate the cachectic phenotype of the PK5L1948 tumor-bearing model. Plasma cytokine and chemokine concentrations were quantified by Luminex assay. High-dimensional flow cytometry was used to investigate changes in tumor-infiltrating immune populations in cachectic miceResults Male tumor-bearing mice exhibited a severely cachectic phenotype, as assessed by >5% decrease in terminal tumor-adjusted body weight and >50% reduction in fat mass. Additionally, PK5L1948 tumors induced significant loss of lean muscle mass and grip strength as well an increase in the liver and spleen masses in males (n=10, p<0.05). Female tumor-bearing mice did not lose muscle mass but demonstrated >30% fat loss and splenomegaly (n=10). The E3 ubiquitin ligase, Fbxo32, was upregulated in skeletal muscles of tumor-bearing mice of both sexes (n=5), corroborating the onset of skeletal muscle atrophy at the molecular level. Plasma cytokine concentrations, particularly TNF and T-cell associated inflammatory mediators were differentially upregulated in males and females (n=10/group, p<0.05), suggesting functional differences in immune cells as potent drivers of sex-bias in PK5L1948-driven cachexia. Importantly we demonstrated the ability of this model to comprehensively investigate the intra-tumoral abundance of various innate and adaptive immune populations, particularly the functional subsets of SIY antigen-specific T cells (effector, memory and exhausted), opening a window of opportunity to test various immunotherapeutic interventions in the cachectic background.Conclusions The PK5L1948 orthotopic PDAC model exhibits prominent hallmarks of cachexia and serves as a novel platform for investigating antigen-specific T cell responses in pancreatic cancer cachexia. Overall, this study has yielded an effective and versatile tool for pre-clinical immunological studies in the context of cachexia.Ethics Approval All animal protocols were approved by the Institutional Animal Care and Use Committee (IACUC) at The Ohio State University (2009A0178-R5) and mice were treated in accordance with institutional guidelines for animal care. The Ohio State University Laboratory Animal Shared Resource is an Association for Assessment and Accreditation of Laboratory Animal Care International accredited program that follows Public Health Service policy and guidelines. All other experiments were completed under the research protocols (2014R00000086; 2013R00000056) approved by the Ohio State University Institutional Biosafety Committee.