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A comprehensive analysis of tumor-stromal collagen in relation to pathological, molecular, and immune characteristics and patient survival in pancreatic ductal adenocarcinoma

Ashina, Shigeto Masuda, Atsuhiro Yamakawa, Kohei Hamada, Tsuyoshi Tsujimae, Masahiro Tanaka, Takeshi Toyama, Hirochika Sofue, Keitaro Shiomi, Hideyuki Sakai, Arata Kobayashi, Takashi Abe, Shohei Gonda, Masanori Masuda, Shigeto Inomata, Noriko Uemura, Hisahiro Kohashi, Shinya Nagao, Kae Harada, Yoshiyuki Miki, Mika Juri, Noriko Irie, Yosuke Kanzawa, Maki Itoh, Tomoo Inoue, Jun Imai, Toshio Fukumoto, Takumi Kodama, Yuzo 神戸大学

2023.10

概要

Background: Abundant collagen deposition is a hallmark of pancreatic ductal adenocarcinomas (PDACs). This study clarified the interactive relationship between tumor-stromal collagen, molecular and immune characteristics, and tumor pr ogression in human PDAC. Methods: We performed a comprehensive examination using an integrative molecular pathological epidemiology database on 169 cases with resected PDAC . The amount of tumor-stromal collagen was quantified through digital imaging analysis for Elastica van Gieson-stained whole-section tumor slides. We analyzed the association of tumor-stromal collagen with gene alterations (KRAS, TP53, CDKN2A/p16, and SMAD4), immune parameters (CD4⁺ tumor-infiltrating lymphocytes [TILs], CD8⁺ TILs, FOXP3⁺ TILs, and tertiary lymphoid structures), and patient prognosis. Results: Low amounts of tumor-stromal collagen were associated with poor differentiation (multivariable OR = 3.82, 95%CI = 1.41–12.2, P = 0.008) and CDKN2A/p16 alteration (OR [95%CI] = 2.06 [1.08–4.02], P = 0.03). Tumors with low collagen levels had shorter overall survival (HR [95%CI] = 2.38 [1.59–3.56], P < 0.0001). In the S-1 and gemcitabine (GEM) treatment groups, low tumor-stromal collagen was linked to poor prognosis of patients with PDAC (S-1 group: multivariable HR [95%CI] = 2.76 [1.36–5.79], P = 0.005; GEM group: multivariate HR [95%CI] = 2.91 [1.34–6.71], P = 0.007). Additionally, low amounts of tumor-stromal collagen were also linked to low levels of CD4⁺ TILs (P = 0.046), CD8⁺ TILs (P = 0.09), and tertiary lymphoid structures (P = 0.001). Conclusions: Tumor-stromal collagen deposition may play a crucial role in modulating tumor-immune microenvironment and determining response to adjuvant chemotherapy and patient survival outcomes.

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参考文献

1. Siegel RL, Miller KD, Fuchs HE, et al. Cancer statistics, 2021.

CA Cancer J Clin. 2021;71:7–33.

2. Provenzano PP, Cuevas C, Chang AE, et al. Enzymatic targeting

of the stroma ablates physical barriers to treatment of pancreatic

ductal adenocarcinoma. Cancer Cell. 2012;21:418–29.

3. Sahai E, Astsaturov I, Cukierman E, et al. A framework for

advancing our understanding of cancer-associated fibroblasts. Nat

Rev Cancer. 2020;20:174–86.

4. Schizas D, Charalampakis N, Kole C, et al. Immunotherapy for

pancreatic cancer: A 2020 update. Cancer Treat Rev. 2020;86:

102016.

5. Jiang H, Hegde S, Knolhoff BL, et al. Targeting focal adhesion

kinase renders pancreatic cancers responsive to checkpoint

immunotherapy. Nat Med. 2016;22:851–60.

6. Balachandran VP, Beatty GL, Dougan SK. Broadening the

impact of immunotherapy to pancreatic cancer: challenges and

opportunities. Gastroenterology. 2019;156:2056–72.

7. Orhan A, Vogelsang RP, Andersen MB, et al. The prognostic

value of tumour-infiltrating lymphocytes in pancreatic cancer: a

systematic review and meta-analysis. Eur J Cancer.

2020;132:71–84.

8. Yao W, Maitra A, Ying H. Recent insights into the biology of

pancreatic cancer. EBioMedicine. 2020;53: 102655.

¨ hlund D, et al. Proteomic analyses of ECM

9. Tian C, Clauser KR, O

during pancreatic ductal adenocarcinoma progression reveal different contributions by tumor and stromal cells. Proc Natl Acad

Sci U S A. 2019;116:19609–18.

10. Neesse A, Algu¨l H, Tuveson DA, et al. Stromal biology and

therapy in pancreatic cancer: a changing paradigm. Gut.

2015;64:1476–84.

11. Chen Y, Kim J, Yang S, et al. Type I collagen deletion in

aSMA? myofibroblasts augments immune suppression and

accelerates progression of pancreatic cancer. Cancer Cell.

2021;39:548-565.e6.

12. Biffi G, Oni TE, Spielman B, et al. IL1-induced JAK/STAT

signaling is antagonized by TGFb to shape CAF heterogeneity in

pancreatic

ductal

adenocarcinoma.

Cancer

Discov.

2019;9:282–301.

J Gastroenterol (2023) 58:1055–1067

13. Olive KP, Jacobetz MA, Davidson CJ, et al. Inhibition of

Hedgehog signaling enhances delivery of chemotherapy in a

mouse model of pancreatic cancer. Science. 2009;324:1457–61.

14. Swartz MA, Lund AW. Lymphatic and interstitial flow in the

tumour microenvironment: linking mechanobiology with immunity. Nat Rev Cancer. 2012;12:210–9.

15. Yu M, Tannock IF. Targeting tumor architecture to favor drug

penetration: a new weapon to combat chemoresistance in pancreatic cancer? Cancer Cell. 2012;21:327–9.

16. Hartmann N, Giese NA, Giese T, et al. Prevailing role of contact

guidance in intrastromal T-cell trapping in human pancreatic

cancer. Clin Cancer Res. 2014;20:3422–33.

¨ zdemir BC, Pentcheva-Hoang T, Carstens JL, et al. Depletion of

17. O

carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival. Cancer Cell. 2014;25:719–34.

18. Rhim AD, Oberstein PE, Thomas DH, et al. Stromal elements act

to restrain, rather than support, pancreatic ductal adenocarcinoma. Cancer Cell. 2014;25:735–47.

19. Lee JJ, Perera RM, Wang H, et al. Stromal response to Hedgehog

signaling restrains pancreatic cancer progression. Proc Natl Acad

Sci U S A. 2014;111:E3091–100.

20. Fukunaga A, Miyamoto M, Cho Y, et al. CD8? tumor-infiltrating

lymphocytes together with CD4? tumor-infiltrating lymphocytes

and dendritic cells improve the prognosis of patients with pancreatic adenocarcinoma. Pancreas. 2004;28:e26-31.

21. Feig C, Jones JO, Kraman M, et al. Targeting CXCL12 from

FAP-expressing carcinoma-associated fibroblasts synergizes with

anti-PD-L1 immunotherapy in pancreatic cancer. Proc Natl Acad

Sci U S A. 2013;110:20212–7.

22. Ene-Obong A, Clear AJ, Watt J, et al. Activated pancreatic

stellate cells sequester CD8? T cells to reduce their infiltration of

the juxtatumoral compartment of pancreatic ductal adenocarcinoma. Gastroenterology. 2013;145:1121–32.

23. Balachandran VP, Łuksza M, Zhao JN, et al. Identification of

unique neoantigen qualities in long-term survivors of pancreatic

cancer. Nature. 2017;551:512–6.

24. Mahajan UM, Langhoff E, Goni E, et al. Immune cell and stromal

signature associated with progression-free survival of patients

with resected pancreatic ductal adenocarcinoma. Gastroenterology. 2018;155:1625-1639.e2.

25. Schumacher TN, Thommen DS. Tertiary lymphoid structures in

cancer. Science. 2022;375:9419.

26. Dieu-Nosjean MC, Giraldo NA, Kaplon H, et al. Tertiary lymphoid structures, drivers of the anti-tumor responses in human

cancers. Immunol Rev. 2016;271:260–75.

27. Hiraoka N, Ino Y, Yamazaki-Itoh R, et al. Intratumoral tertiary

lymphoid organ is a favourable prognosticator in patients with

pancreatic cancer. Br J Cancer. 2015;112:1782–90.

28. Kuwabara S, Tsuchikawa T, Nakamura T, et al. Prognostic relevance of tertiary lymphoid organs following neoadjuvant

chemoradiotherapy in pancreatic ductal adenocarcinoma. Cancer

Sci. 2019;110:1853–62.

29. Waddell N, Pajic M, Patch AM, et al. Whole genomes redefine

the mutational landscape of pancreatic cancer. Nature.

2015;518:495–501.

30. Qian ZR, Rubinson DA, Nowak JA, et al. Association of alterations in main driver genes with outcomes of patients with

resected pancreatic ductal adenocarcinoma. JAMA Oncol.

2018;4:e173420.

31. Tanaka T, Masuda A, Inoue J, et al. Integrated analysis of tertiary

lymphoid structures in relation to tumor-infiltrating lymphocytes

and patient survival in pancreatic ductal adenocarcinoma. J Gastroenterol. 2023;58:277–91.

1067

32. Mazaika E, Homsy J. Digital droplet PCR: CNV analysis and

other applications. Curr Protoc Hum Genet. 2014;82:7–24.

33. Lassaletta A, Zapotocky M, Mistry M, et al. Therapeutic and

prognostic implications of BRAF V600E in pediatric low-grade

gliomas. J Clin Oncol. 2017;35:2934–41.

34. Carapuc¸a EF, Gemenetzidis E, Feig C, et al. Anti-stromal treatment together with chemotherapy targets multiple signalling

pathways

in

pancreatic

adenocarcinoma.

Pathol.

2016;239:286–96.

35. Simianu VV, Zyromski NJ, Nakeeb A, et al. Pancreatic cancer:

progress made. Acta Oncol. 2010;49:407–17.

36. Tang Y, Xu X, Guo S, et al. An increased abundance of tumorinfiltrating regulatory T cells is correlated with the progression

and prognosis of pancreatic ductal adenocarcinoma. PLoS ONE.

2014;9:e91551.

37. Sato E, Olson SH, Ahn J, et al. Intraepithelial CD8? tumorinfiltrating lymphocytes and a high CD8?/regulatory T cell ratio

are associated with favorable prognosis in ovarian cancer. Proc

Natl Acad Sci U S A. 2005;102:18538–43.

38. Ahmed A, Ko¨hler S, Klotz R, et al. Tertiary lymphoid structures

and their association to immune phenotypes and circulatory IL2

levels in pancreatic ductal adenocarcinoma. Oncoimmunology.

2022;11:2027148.

39. Hwang RF, Moore T, Arumugam T, et al. Cancer-associated

stromal fibroblasts promote pancreatic tumor progression. Cancer

Res. 2008;68:918–26.

40. Erkan M, Reiser-Erkan C, Michalski CW, et al. Cancer-stellate

cell interactions perpetuate the hypoxia-fibrosis cycle in pancreatic ductal adenocarcinoma. Neoplasia. 2009;11:497–508.

41. Ikenaga N, Ohuchida K, Mizumoto K, et al. CD10? pancreatic

stellate cells enhance the progression of pancreatic cancer. Gastroenterology. 2010;139(1041–51):51.e1-8.

42. Mantoni TS, Lunardi S, Al-Assar O, et al. Pancreatic stellate cells

radioprotect pancreatic cancer cells through b1-integrin signaling. Cancer Res. 2011;71:3453–8.

43. Jiang N, Qiao G, Wang X, et al. Dendritic cell/cytokine-induced

killer cell immunotherapy combined with S-1 in patients with

advanced pancreatic cancer: A prospective study. Clin Cancer

Res. 2017;23:5066–73.

44. Vincent J, Mignot G, Chalmin F, et al. 5-fluorouracil selectively

kills tumor-associated myeloid-derived suppressor cells resulting

in enhanced T cell-dependent antitumor immunity. Cancer Res.

2010;70:3052–61.

45. Ogawa Y, Masugi Y, Abe T, et al. Three distinct stroma types in

human pancreatic cancer identified by image analysis of fibroblast subpopulations and collagen. Clin Cancer Res.

2021;27:107–19.

46. Luo C, Zhou S, Zhou Z, et al. Wnt9a promotes renal fibrosis by

accelerating cellular senescence in tubular epithelial cells. J Am

Soc Nephrol. 2018;29:1238–56.

47. Lehmann M, Korfei M, Mutze K, et al. Senolytic drugs target alveolar epithelial cell function and attenuate experimental

lung fibrosis ex vivo. Eur Respir J. 2017;50:1602367.

48. Wang HQ, Li Y, Song X, et al. Significance of interstitial fibrosis

and p16 in papillary thyroid carcinoma. Endocr J.

2022;69:1253–9.

49. Lv F, Li N, Kong M, et al. CDKN2a/p16 antagonizes hepatic

stellate cell activation and liver fibrosis by modulating ROS

Levels. Front Cell Dev Biol. 2020;8:176.

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