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. 2024 May 10;22(1):443.
doi: 10.1186/s12967-024-05252-1.

Keratin 17 modulates the immune topography of pancreatic cancer

Lyanne Delgado-Coka  1   2 , Michael Horowitz  1 , Mariana Torrente-Goncalves  1 , Lucia Roa-Peña  1   3 , Cindy V Leiton  1 , Mahmudul Hasan  4 , Sruthi Babu  1 , Danielle Fassler  1 , Jaymie Oentoro  1 , Ji-Dong K Bai  1 , Emanuel F Petricoin 3rd  5   6 , Lynn M Matrisian  7 , Edik Matthew Blais  6 , Natalia Marchenko  1 , Felicia D Allard  8 , Wei Jiang  9 , Brent Larson  10 , Andrew Hendifar  10 , Chao Chen  11 , Shahira Abousamra  4 , Dimitris Samaras  4 , Tahsin Kurc  11 , Joel Saltz #  12   13 , Luisa F Escobar-Hoyos #  14   15   16   17 , Kenneth R Shroyer #  18
Affiliations

Keratin 17 modulates the immune topography of pancreatic cancer

Lyanne Delgado-Coka et al. J Transl Med. .

Abstract

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.

Keywords: Cancer biomarker; Cancer immunology; Digital pathology; Immune microenvironment; Keratin 17; Multiplexed immunohistochemistry; Pancreatic ductal adenocarcinoma.

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Conflict of interest statement

KRS and LEH are consultants to KDx Diagnostics Inc. EB is an employee of Perthera and owns stock in the company. EFP has received compensation as an officer of Perthera, Inc. and owns stock in the company. He has also consulted for Theralink Technologies, Inc. and received compensation as Chair of their Science Advisory Board and owns stock in the company. Other authors report no competing interests with the current study.

Figures

Fig. 1
Fig. 1
Analysis of Keratin 17 relative to the PDAC immune microenvironment. a Overall fraction of immune cell types averaged across all cases (n = 235). b Spearman correlation between manual and digital K17 scoring across entire tumor sections. c. Overall immune cells stacked bar plot including CD4+ T cells, CD8+ T cells, CD16+ macrophage, and CD163+ macrophage density (cells/mm2). The right Y-axis depicts the overall K17 score within each tumor. d Development of a digital scoring system focused on spatial relationships between peritumoral and intratumoral immune cells and K17. Intratumoral zones were defined as those that directly contacted a tumor cell while peritumoral zones included only immune cells within 25 μm of the closest tumor cell boundary
Fig. 2
Fig. 2
K17 impacts intratumoral and peritumoral T cells and macrophages. a–h T cell counts in peritumoral and intratumoral K17-positive and K17-negative regions. a Peritumoral CD8+ T cells. c Intratumoral CD8+ T cells. e Peritumoral CD4+ T cells. g Intratumoral CD4+ T cells. i–p Macrophage counts in peritumoral and intratumoral K17-negative regions relative to K17-positive regions. i Peritumoral CD16+ macrophages; k Intratumoral CD16+ macrophages; m peritumoral CD163+ macrophages; o intratumoral CD163+ macrophages. Representative mIHC images for each panel highlight intratumor and peritumor b, d CD8+ T cells (purple); f, h CD4+ T cells (red); j, l CD16+ macrophages (yellow) and; n, p CD163+ macrophages (green) relative to K17-positive tumor cells (brown) and K17-negative tumor cells (teal). Note that immune cell ratios are normalized to counts in K17-positive zones and relative height of the bars reflects the magnitude of differences between ratios in K17-negative versus K17-positive zones, not relative differences in overall immune cell counts
Fig. 3
Fig. 3
The impact of K17 on CD8+ T Cells is independent of neoadjuvant therapy. a, b Peritumoral and intratumoral CD8+ T cell density ratios in cases that did not receive neoadjuvant treatment and, c, d cases treated with neoadjuvant treatment
Fig. 4
Fig. 4
The impact of K17 on CD8+ T cells is independent of PDAC stage, grade, and lymph node status. Immune cell ratios in peritumoral and intratumoral K17-negative regions relative to K17-positive regions, ordered based on the density of immune cells in K17-positive zones. The inverse correlation between K17 expression and CD8+ peritumor and intratumoral T cells is independent of a–d stage, e–h tumor grade, and i–l Lymph node status
Fig. 5
Fig. 5
CD8+ T cells are increased in K17-negative regions, regardless of mutation status. Immune cell ratios in peritumoral and intratumoral K17-negative regions relative to K17-positive regions and mutational status of KRAS, p53, SMAD4, and CDKN2A. a OncoPrint [8, 12, 18] depicting the most frequently mutated genes in the KYT cohort. b–q Wild type versus mutant KRAS, p53, SMAD4, and CDKN2A
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References

    1. Achanta R, Shaji A, Smith K, Lucchi A, Fua P, Süsstrunk S. SLIC superpixels compared to stateof-the-art superpixel methods. IEEE Trans Pattern Anal Mach Intell. 2012;34(11):2274–82. 10.1109/TPAMI.2012.120. - PubMed
    1. Adsay V, Logani S, Sarkar F, Crissman J, Vaitkevicius V. Foamy gland pattern of pancreatic ductal adenocarcinoma: a deceptively benign-appearing variant. Am J Surg Pathol. 2000;24(4):493–504. 10.1097/00000478-200004000-00003. - PubMed
    1. Amin MB, Greene FL, Edge SB, Compton CC, Gershenwald JE, Brookland RK, Meyer L, Gress DM, Byrd DR, Winchester DP. The eighth edition AJCC cancer staging manual: continuing to build a bridge from a population-based to a more “personalized” approach to cancer staging. CA Cancer J Clin. 2017;67(2):93–99. doi: 10.3322/CAAC.21388. - DOI - PubMed
    1. Bailey P, Chang DK, Forget MA, Lucas FAS, Alvarez HA, Haymaker C, Chattopadhyay C, Kim SH, Ekmekcioglu S, Grimm EA, Biankin AV, Hwu P, Maitra A, Roszik J. Exploiting the neoantigen landscape for immunotherapy of pancreatic ductal adenocarcinoma. Sci Rep. 2016;6(1):1–8. doi: 10.1038/srep35848. - DOI - PMC - PubMed
    1. Baraks G, Tseng R, Pan CH, Kasliwal S, Leiton CV, Shroyer KR, Escobar-Hoyos LF. Dissecting the oncogenic roles of keratin 17 in the hallmarks of cancer. Cancer Res. 2022;82(7):1159–1166. doi: 10.1158/0008-5472.CAN-21-2522. - DOI - PMC - PubMed

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