What question did this study set out to answer?

To investigate the effects of MTAP deficiency on the immune landscape and proliferation in pancreatic ductal adenocarcinoma.

April 5, 2026

Abstract 7404: MTAP loss reshapes the immune and proliferative landscape of pancreatic ductal adenocarcinoma

Key Points

To investigate the effects of MTAP deficiency on the immune landscape and proliferation in pancreatic ductal adenocarcinoma.
Analyzed 378 pancreatic ductal adenocarcinomas using an 8-marker multiplex immunohistochemistry approach.
Assessed immune cell infiltration and tumor cell proliferation in relation to MTAP status.
Compared clinical parameters like tumor stage and grade with immune cell density.
Utilized statistical analyses to determine significance of findings.
MTAP deficiency was associated with higher densities of CD68+ macrophages compared to MTAP-retained tumors.
Proliferative lymphocytes were significantly enriched in MTAP-loss tumors.
Overall tumor cell proliferation was elevated in MTAP-loss cases, indicating increased labeling indices in various cell-cycle phases.
Early-stage MTAP-loss tumors demonstrated higher lymphocyte densities than advanced stages.
Lower-grade tumors exhibited higher densities of proliferative lymphocytes in MTAP-retained cases.

Abstract

Abstract 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. Citation Format: Elena Bady, Jan H. Müller, Ronald Simon, Christian Bernreuther, Nina Schraps, Fiete Gehrisch, Natalia Gorbokon, Florian Viehweger, Frank Jacobsen, Guido Sauter, Katharina Möller, Andreas Lübke, Andrea Hinsch, Till S. Clauditz, Eike C. Burandt, Zhihao Huang. MTAP loss reshapes the immune and proliferative landscape of pancreatic ductal adenocarcinoma abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7404.

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