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Background: PDAC is an aggressive and treatment-refractory cancer due to its desmoplastic and immunosuppressive tumor microenvironment (TME). Overexpression of pFAK, a master regulator of the TME, and CXCR4, a receptor involved immunosuppression and tumor progression, are associated with poorer outcomes in PDAC. Exceptional responders, broadly defined by extended survival and durable treatment responses, represent a rare subset in PDAC. We hypothesize that the immune and stromal signatures of exceptional responders vary significantly from non-exceptional responders, specifically exhibiting decreased p-FAK and CXCR4 expression and decreased immunosuppressive myeloid phenotypes in the TME. Methods: We performed correlative quantitative analysis of multiplex immunohistochemistry (mIHC) employing 40 biomarkers on stage I/II PDAC, surgically resected formalin-fixed paraffin-embedded tissues from 9 non-exceptional responders and 11 exceptional responders. Exceptional responders were selected based on degree and duration of disease-free survival or overall survival more than double the historical matched medians. mIHC and image cytometry were used to distinguish and quantify total immune cell populations and colocalize biomarker expression across each distinct cell type. Cell populations and expression levels were compared using unpaired T-tests. Results: Exceptional responders showed significantly decreased overall pFAK expression (p=0.02) and overall CXCR4 expression (p=0.04). In exceptional responders, pFAK expression and CXCR4 expression were significantly decreased in immunosuppressive CD66b+ granulocytes (p=0.01, p=0.03, respectively) and in tumor associated macrophages (p=0.01, p=0.006, respectively). While not significant, exceptional responders demonstrated a marked decrease in immunosuppressive pFAK+ fibroblasts (p=0.12) when compared to non-exceptional responders. No change was seen in the CD8+ T cell infiltration between groups; however, a trend was observed towards an increased proportion of granzyme B+ CD3+ CD8+ cytotoxic lymphocytes (p=0.57) in exceptional responders. Conclusion: Exceptional responders selected in this preliminary study have significantly lower FAK and CXCR4 expression and markedly reduced populations of immunosuppressive FAK+ and CXCR4+ myeloid cells. Suppression of pFAK and CXCR4 in fibroblasts and granulocytes, respectively are associated with exceptional clinical outcomes. Future expanded research comparing the distinct TME and genetic signatures of exceptional responders to non-exceptional is warranted. Citation Format: John Davelaar, Anser A. Abbas, Angela Minasyan, Omer H. Elmadbouh, Natalie Moshayedi, Brent Larson, Nicholas Nissen, Simon Lo, Srinivas Gaddam, Kambiz Kosari, Jun Gong, Andrew Hendifar, Stephen Pandol, Arsen Osipov. Suppression of phosphorylated focal adhesion kinase+ (pFAK+) fibroblasts and C-X-C chemokine receptor type 4 (CXCR4) expressing granulocytes is associated with exceptional clinical outcomes in pancreatic ductal adenocarcinoma (PDAC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5854.