Clonal Phenotype Mapping Reveals Genomic Alterations Underlying Tumor Immunosuppression during Immunotherapy

<p>Tumors are dynamic ecosystems that evolve under selective pressures, shaping their ability to either elicit or evade immune responses. In pancreatic ductal adenocarcinoma (PDAC), where immunotherapy has yet to become an effective treatment option, we investigated the role of intratumoral heterogeneity in influencing immune interactions. Using orthotopic clonal replica tumors, we tracked clonal dynamics in response to anti-PD1 therapy and found that while treatment had limited impact on overall tumor volume, it induced profound shifts in clonal composition. Spatial lineage analysis of treatment-naïve tumors revealed that clones with distinct immunotherapy sensitivities occupy unique tumor microenvironments, a pattern that remained stable across independent tumors due to the ability of tumor clones to reprogram their surroundings. Further analysis identified a recurrent genomic alteration associated with an immunosuppressive immune microenvironment, which correlates with poor immunotherapy response and is conserved across multiple cancer types. These findings highlight the intrinsic stability of tumor immunogenicity at the clonal level and provide insights into potential predictive markers for immunotherapy resistance.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation (PhD)

Year dc:date.available

2025

Authors dc:creator

• Yen, Er-Yen
• <p>0000-0003-2918-5419</p>

Contributors dc:contributor

• Giulio Draetta
• Andrea Viale
• Stephanie Watowich

• tumor heterogeneity
• clonal evolution
• immunoediting
• molecular barcoding
• multiplexed imaging
• microenvironment
• crosstalk
• resistance; Immunotherapy
• Cancer Biology

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/1463

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-2520