S82 Longitudinal Immunoprofiling of Pancreatic Cancer Patients to Identify Mediators of Therapy Resistance

Carpenter, Eileen S.; Kemp, Samantha B.; Kadiyala, Padma; Steele, Nina G.; Elhossiny, Ahmed M.; Sirihorachai, Veerin R.; Du, Wenting; Espinoza, Carlos; The, Stephanie; Freeman, Julia; Bhalla, Sean; Singhvi, Ajay; Anderson, Michelle A.; Kwon, Richard S.; Wamsteker, Erik–Jan; Prabhu, Anoop; Schulman, Allison R.; Gunchick, Valerie; Sahai, Vaibhav; Bednar, Filip; Magliano, Marina Pasca di

doi:10.14309/01.ajg.0000772308.12601.74

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“…Therefore, advancing our understanding of the immunobiology of PDAC by identifying new targets and biomarkers predicting immunotherapy response is crucial for improving clinical outcomes. Although K17 impacts numerous hallmarks of cancer [5] and has been established as a defining biomarker of the basal molecular subtypes of pancreatic cancer [35,46,47] emerging clinical and research data support its mechanistic role in the regulation of the immune response [5,6].…”

Section: Discussionmentioning

confidence: 99%

“…Similarly, in head and neck squamous cell carcinoma, the knockout of K17 in immunocompetent mouse model also resulted in tumor regression due to alterations in IFN -γ and CXCL9, and PD-L1 expression and increased CD8+ T-cell infiltration, thereby sensitizing tumors to immune-checkpoint blockade [59]. In PDAC, single-cell RNA seq analysis of 18 human biopsies identified a population of cells with high KRT17, CXCL8, and multiple other inflammatory cytokines, inducing the emergence of immunosuppressive immune cell populations [6]. Consistent with these observations, Raghavan et al [44] identified TGF-β signaling by single-cell RNA seq analysis as a top-upregulated pathway in basal subtype PDAC, associated with exclusion of both CD8+ and CD4+ T cells from the tumor microenvironment.…”

Section: Discussionmentioning

confidence: 99%

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Keratin 17 modulates the immune topography of pancreatic cancer

Delgado-Coka,

Horowitz,

Torrente-Goncalves

et al. 2024

J Transl Med

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Background The immune microenvironment impacts tumor growth, invasion, metastasis, and patient survival and may provide opportunities for therapeutic intervention in pancreatic ductal adenocarcinoma (PDAC). Although never studied as a potential modulator of the immune response in most cancers, Keratin 17 (K17), a biomarker of the most aggressive (basal) molecular subtype of PDAC, is intimately involved in the histogenesis of the immune response in psoriasis, basal cell carcinoma, and cervical squamous cell carcinoma. Thus, we hypothesized that K17 expression could also impact the immune cell response in PDAC, and that uncovering this relationship could provide insight to guide the development of immunotherapeutic opportunities to extend patient survival. Methods Multiplex immunohistochemistry (mIHC) and automated image analysis based on novel computational imaging technology were used to decipher the abundance and spatial distribution of T cells, macrophages, and tumor cells, relative to K17 expression in 235 PDACs. Results K17 expression had profound effects on the exclusion of intratumoral CD8+ T cells and was also associated with decreased numbers of peritumoral CD8+ T cells, CD16+ macrophages, and CD163+ macrophages (p < 0.0001). The differences in the intratumor and peritumoral CD8+ T cell abundance were not impacted by neoadjuvant therapy, tumor stage, grade, lymph node status, histologic subtype, nor KRAS, p53, SMAD4, or CDKN2A mutations. Conclusions Thus, K17 expression correlates with major differences in the immune microenvironment that are independent of any tested clinicopathologic or tumor intrinsic variables, suggesting that targeting K17-mediated immune effects on the immune system could restore the innate immunologic response to PDAC and might provide novel opportunities to restore immunotherapeutic approaches for this most deadly form of cancer.

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