MTAP loss reshapes the immune and proliferative landscape of pancreatic ductal adenocarcinoma

S-methyl-5′-thioadenosine phosphorylase (MTAP) is encoded by the MTAP gene located at 9p21 and is often homozygously co-deleted in cancer together with cyclin dependent kinase 2A (CDKN2A). As a result, MTAP deficiency results in a critical vulnerability of cancer cells towards drugs targeting multiple pathways. MTAP deficiency has also been found to predict poor response to immune checkpoint inhibitors. Ductal adenocarcinoma of the pancreas belongs to a group of tumors with a particularly high rate of MTAP deficiencies. To learn more on potential differences in the tumor-microenvironment and proliferative activity between MTAP deficient and proficient cancers, a tissue microarray containing 378 pancreatic ductal adenocarcinomas were analyzed by an 8-marker multiplex immunohistochemistry approach. With respect to innate immune infiltration, MTAP loss was associated with significantly higher densities of CD68⁺ macrophages compared to MTAP-retained tumors (p = 0.010), an effect predominantly driven by stromal CD68⁺PanCK⁻ macrophages (p = 0.005). In contrast, total lymphocyte densities (CD45⁺CD68⁻PanCK⁻) showed only a mild, non-significant increase in MTAP-loss tumors. However, proliferative lymphocytes within the tumor compartment (CD45⁺CD68⁻MCM3⁺Ki67⁺PanCK⁺) were significantly enriched in MTAP-loss cases (p = 0.018), while proliferative intraepithelial lymphocytes lacking Ki67 (CD45⁺CD68⁻MCM3⁺PanCK⁺) showed a trend toward higher density (p = 0.052). Tumor cell proliferative activity was consistently elevated in MTAP-loss tumors, reflected by significantly increased labeling indices in very early (Ki67⁺MCM3⁺; p = 0.004), early (MCM3⁺; p = 0.007), and intermediate (Ki67⁺MCM3⁺; p = 0.030) cell-cycle phases. Clinicopathological parameters further modulated these associations. Early-stage tumors (pT1-2) displayed higher lymphocyte densities than pT3-4 tumors (p = 0.025), particularly in MTAP-loss cases, whereas MTAP-retained tumors showed higher densities of proliferating macrophages in pT1-2 than in pT3-4 lesions (p < 0.001). Nodal-negative tumors (pN0) exhibited higher intraepithelial lymphocyte (p = 0.044) and proliferative lymphocyte (p = 0.036) densities than pN⁺ tumors, most prominently in MTAP-retained cases. Similarly, lower-grade tumors (Grade 1-2) demonstrated significantly higher intraepithelial proliferative lymphocyte densities (p < 0.005) compared to Grade 3 tumors, again largely restricted to MTAP-retained cancers. It is concluded, that MTAP deficiency impacts the immune microenvironment of pancreatic ductal adenocarcinoma by promoting stromal macrophage accumulation and increased proliferation within immune and tumor compartments.