Browsing by Author "Wang, Huamin"

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    Diminished Immune Surveillance during Histologic Progression of Intraductal Papillary Mucinous Neoplasms Offers a Therapeutic Opportunity for Cancer Interception
    (American Association for Cancer Research, 2022) Hernandez, Sharia; Parra, Edwin Roger; Uraoka, Naohiro; Tang, Ximing; Shen, Yu; Qiao, Wei; Jiang, Mei; Zhang, Shanyu; Mino, Barbara; Lu, Wei; Pandurengan, Renganayaki; Haymaker, Cara; Affolter, Kajsa; Scaife, Courtney L.; Yip-Schneider, Michele; Schmidt, C. Max; Firpo, Matthew A.; Mulvihill, Sean J.; Koay, Eugene J.; Wang, Huamin; Wistuba, Ignacio I.; Maitra, Anirban; Solis, Luisa M.; Sen, Subrata; Surgery, School of Medicine
    Purpose: Intraductal papillary mucinous neoplasms (IPMN) are bona fide precursors to pancreatic ductal adenocarcinoma (PDAC). While genomic alterations during multistep IPMN progression have been well cataloged, the accompanying changes within the tumor immune microenvironment (TIME) have not been comprehensively studied. Herein, we investigated TIME-related alterations during IPMN progression, using multiplex immunofluorescence (mIF) coupled with high-resolution image analyses. Experimental design: Two sets of formalin-fixed, paraffin-embedded tissue samples from surgically resected IPMNs were analyzed. The training set of 30 samples consisted of 11 low-grade IPMN (LG-IPMN), 17 high-grade IPMN (HG-IPMN), and 2 IPMN with PDAC, while a validation set of 93 samples comprised of 55 LG-IPMN and 38 HG-IPMN. The training set was analyzed with two panels of immuno-oncology-related biomarkers, while the validation set was analyzed with a subset of markers found significantly altered in the training set. Results: Cell types indicative of enhanced immune surveillance, including cytotoxic and memory T cells, and antigen-experienced T cells and B cells, were all found at higher densities within isolated LG-IPMNs compared with HG-IPMNs. Notably, the TIME of LG-IPMNs that had progressed at the time of surgical resection (progressor LGD) resembled that of the synchronous HG-IPMNs, underscoring that attenuated immune surveillance occurs even in LG-IPMNs destined for progression. Conclusions: Our findings provide a basis for interception of cystic neoplasia to PDAC, through maintenance of sustained immune surveillance using vaccines and other prevention approaches.
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    Targeting T cell checkpoints 41BB and LAG3 and myeloid cell CXCR1/CXCR2 results in antitumor immunity and durable response in pancreatic cancer
    (Springer Nature, 2023) Gulhati, Pat; Schalck, Aislyn; Jiang, Shan; Shang, Xiaoying; Wu, Chang-Jiun; Hou, Pingping; Hernandez Ruiz, Sharia; Solis Soto, Luisa; Parra, Edwin; Ying, Haoqiang; Han, Jincheng; Dey, Prasenjit; Li, Jun; Deng, Pingna; Sei, Emi; Maeda, Dean Y.; Zebala, John A.; Spring, Denise J.; Kim, Michael; Wang, Huamin; Maitra, Anirban; Moore, Dirk; Clise-Dwyer, Karen; Wang, Y. Alan; Navin, Nicholas E.; DePinho, Ronald A.; Medicine, School of Medicine
    Pancreatic ductal adenocarcinoma (PDAC) is considered non-immunogenic, with trials showing its recalcitrance to PD1 and CTLA4 immune checkpoint therapies (ICTs). Here, we sought to systematically characterize the mechanisms underlying de novo ICT resistance and to identify effective therapeutic options for PDAC. We report that agonist 41BB and antagonist LAG3 ICT alone and in combination, increased survival and antitumor immunity, characterized by modulating T cell subsets with antitumor activity, increased T cell clonality and diversification, decreased immunosuppressive myeloid cells and increased antigen presentation/decreased immunosuppressive capability of myeloid cells. Translational analyses confirmed the expression of 41BB and LAG3 in human PDAC. Since single and dual ICTs were not curative, T cell-activating ICTs were combined with a CXCR1/2 inhibitor targeting immunosuppressive myeloid cells. Triple therapy resulted in durable complete responses. Given similar profiles in human PDAC and the availability of these agents for clinical testing, our findings provide a testable hypothesis for this lethal disease.