Smad deficiency impacts chemotherapeutic responses through alterations in immuno-stromal microenvironment of pancreatic adenocarcinoma

Background: Pancreatic adenocarcinoma (PDAC) is a devastating cancer with a dismal prognosis. Preoperative chemotherapy (PreOP_CT) has reshaped the treatment paradigm. However, factors influencing therapeutic responses and immune/stromal alterations have not been established. Smad family exerts pivotal biological actions through transforming growth factor-beta (TGFbeta) axis and affects tumor microenvironment (TME), yet the correlation with therapeutic responses has not been fully explored. Methods: We explored a prospective cohort of patients with resectable PDAC who received PreOP_CT. Genomic aberrations of the Smad family in the TGFbeta axis were assessed and compared for clinical outcomes. Single-cell RNA sequencing delineated the immuno-stromal alterations in Smad-deficient vs. -proficient tumors. Results: Fifteen of 106 patients had Smad-deficient tumors and showed reduced tumor regression, higher metastatic progression and adverse survival as compared with -proficient ones. SMAD4 or TGFBR2/3 mutations were observed in Smad-deficient tumors. Smad deficiency correlated with different enrichments of tumor-infiltrating immune cells (TIMCs) and cancer-associated fibroblasts (CAFs). Collectively, inflammatory and antigen-presenting CAFs were distinctive in the deficient tumors and presented with immune evasive actions. Conclusion: Smad deficiency influences therapeutic and surgical outcomes in PreOP_CT-treated PDAC. The Smad family potentially affects TIMCs and CAFs, potentiating an immune evasive and profibrotic TME. The results provide insight into a putative biomarker for PreOP therapies in PDAC.