Tumor‑infiltrating lymphocytes in tissue material combined with systemic lymphocyte inflammation in patients with colorectal cancer

Jakubowska,Katarzyna; Koda,Mariusz; Grudzińska,Małgorzata; Lomperta,Karolina; Famulski,Waldemar

doi:10.3892/mco.2021.2259

Tumor‑infiltrating lymphocytes in tissue material combined with systemic lymphocyte inflammation in patients with colorectal cancer

Authors:
- Katarzyna Jakubowska
- Mariusz Koda
- Małgorzata Grudzińska
- Karolina Lomperta
- Waldemar Famulski
View Affiliations

Affiliations: Department of Pathomorphology, Comprehensive Cancer Center, 15‑027 Bialystok, Poland, Department of General Pathomorphology, Medical University of Bialystok, 15‑269 Bialystok, Poland, Department of Medical Pathomorphology, Medical University of Bialystok, 15‑269 Bialystok, Poland
Published online on: March 12, 2021 https://doi.org/10.3892/mco.2021.2259
Article Number: 97

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The efficacy of cancer immunotherapy has been actively explored in the treatment of various malignant neoplasms of the gastrointestinal tract. In light of recent reports, the present study aimed to investigate the combination of the absolute lymphocyte count (ALC), percentage of tumor‑infiltrating lymphocyte (TILs) and tumor progression status in patients with colorectal cancer (CRC) who underwent surgery. The medical records of 160 patients diagnosed with CRC were retrospectively reviewed. TILs were determined as a percentage of mononuclear inflammatory cells in the total intratumoral or stromal area as determined in five high power fields (magnification, x200‑400), at the invasive front and in the centre of the tumour. Blood samples were obtained within 3 days prior to and 7 days following the surgical treatment. The assessment of the TIL percentage was performed in the tissue at the invasive front and in the centre of the primary tumour mass in combination with the determination of ALC in whole blood samples. The samples were obtained prior to and after surgery from patients with CRC, and the tumour progression status was also assessed (TILs/ALC/tumour progression status). A significant association was observed between the percentage of TILs in the main mass of tumour and the tumour size (P=0.031), the pT stage (P=0.049) and the incidence of necrosis (P=0.037) following surgery. The histological type was associated with the evaluated combined parameters prior to surgery (P=0.046). Lymph node pouch invasion was associated with TILs at the invasive front of tumour and with ALC prior to and after surgery (P=0.006 and P=0.037). Furthermore, the data indicated that the percentage of TILs located on the invasive front and centre of the tumour, and the ALC prior to and following surgery correlated with the treatment status (P=0.032, P=0.018, P≤0.001 and P≤0.001). A significant association was noted between eight features and evaluated combined parameters following surgery. These included the tumour size (P=0.021), TNM stage (P<0.001), tumour deposits (P=0.001), incidence of necrosis (P=0.042) and lymph node metastasis (P<0.001). Furthermore, the degree of invasion of venous (P<0.001), lymphatic (P<0.001) and perineural (P<0.001) sites was also significantly associated with TILs, ALC obtained after surgical treatment and tumor progression status. The data demonstrated that local and systemic chronic inflammation was associated with tumour progression in patients with CRC.

View Figures

View References

1	Ando K, Hamada K, Watanabe M, Ohkuma R, Shida M, Onoue R, Kubota Y, Matsui H, Ishiguro T, Hirasawa Y, et al: Plasma levels of soluble PD-L1 correlate with tumor regression in patients with lung and gastric cancer treated with immune checkpoint inhibitors. Anticancer Res. 39:5195–5201. 2019.PubMed/NCBI View Article : Google Scholar
2	Badran YR, Cohen JV, Brastianos PK, Parikh AR, Hong TS and Dougan M: Concurrent therapy with immune checkpoint inhibitors and TNFα blockade in patients with gastrointestinal immune-related adverse events. J Immunother Cancer. 7(226)2019.PubMed/NCBI View Article : Google Scholar
3	Fan Y and Moon JJ: Nanoparticle drug delivery systems designed to improve cancer vaccines and immunotherapy. Vaccines (Basel). 3:662–685. 2015.PubMed/NCBI View Article : Google Scholar
4	Xiong Y, Wang Y and Tiruthani K: Tumor immune microenvironment and nano-immunotherapeutics in colorectal cancer. Nanomedicine. 21(102034)2019.PubMed/NCBI View Article : Google Scholar
5	Compton CC: Colorectal carcinoma: Diagnostic, prognostic, and molecular features. Mod Pathol. 16:376–388. 2003.PubMed/NCBI View Article : Google Scholar
6	Guinney J, Dienstmann R, Wang X, de Reyniès A, Schlicker A, Soneson C, Marisa L, Roepman P, Nyamundanda G, Angelino P, et al: The consensus molecular subtypes of colorectal cancer. Nat Med. 21:1350–1356. 2015.PubMed/NCBI View Article : Google Scholar
7	Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, Skora AD, Luber BS, Azad NS, Laheru D, et al: PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 372:2509–2520. 2015.PubMed/NCBI View Article : Google Scholar
8	Norton SE, Ward-Hartstonge KA, Taylor ES and Kemp RA: Immune cell interplay in colorectal cancer prognosis. World J Gastrointest Oncol. 7:221–232. 2015.PubMed/NCBI View Article : Google Scholar
9	Laghi L, Bianchi P, Miranda E, Balladore E, Pacetti V, Grizzi F, Allavena P, Torri V, Repici A, Santoro A, et al: CD3⁺ cells at the invasive margin of deeply invading (pT3-T4) colorectal cancer and risk of post-surgical metastasis: A longitudinl study. Lancet Oncol. 10:877–884. 2009.PubMed/NCBI View Article : Google Scholar
10	Bindea G, Mlecnik B, Tosolini M, Kirilovsky A, Waldner M, Obenauf AC, Angell H, Fredriksen T, Lafontaine L, Berger A, et al: Spatiotemporal dynamics of intratumoral immune cells reveal the immune landscape in human cancer. Immunity. 39:782–795. 2013.PubMed/NCBI View Article : Google Scholar
11	Tanio A, Saito H, Uejima C, Takaya S, Yamamoto M, Tokuyasu N, Sakamoto T, Honjo S, Ashida K and Fujiwara Y: A prognostic index for colorectal cancer based on preoperative absolute lymphocyte, monocyte, and neutrophil counts. Surg Today. 49:245–253. 2019.PubMed/NCBI View Article : Google Scholar
12	Kozak MM, von Eyben R, Pai JS, Anderson EM, Welton ML, Shelton AA, Kin C, Koong AC and Chang DT: The prognostic significance of pretreatment hematologic parameters in patients undergoing resection for colorectal cancer. Am J Clin Oncol. 4:405–412. 2017.PubMed/NCBI View Article : Google Scholar
13	Yang L, He W, Kong P, Jiang C, Yang Q, Xie Q and Xia LP: Clinical baseline and prognostic difference of platelet lymphocyte ratio (PLR) in right-sided and let-sided colon cancers. BMC Cancer. 17(873)2017.PubMed/NCBI View Article : Google Scholar
14	Hamilton SR and Aaltonen LA: Tumors of the colon and rectum. In: World Health Organization Classification of Tumors. Pathology and Genetics of Tumours of the Digestive System. Lyon, IARC Press, pp103-104, 2000.
15	Lin Q, Wei Y, Ren L, Zhong Y, Qin C, Zheng P, Xu P, Zhu D, Ji M and Xu J: Tumor deposit is a poor prognostic indicator in patients who underwent simultaneous resection for synchronous colorectal liver metastases. Onco Targets Ther. 8:233–240. 2015.PubMed/NCBI View Article : Google Scholar
16	Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC and Gwyther SG: New guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer Inst. 92:205–216. 2000.PubMed/NCBI View Article : Google Scholar
17	Jakubowska K, Kisielewski W, Kańczuga-Koda L, Koda M and Famulski W: Stromal and intraepithelial tumour-infiltrating lymphocytes in colorectal carcinoma. Oncol Lett. 14:6421–6432. 2017.PubMed/NCBI View Article : Google Scholar
18	Salgado R, Denkert C, Demaria S, Sirtaine N, Klauschen F, Pruneri G, Wienert S, Van den Eynden G, Baehner FL, Penault-Llorca F, et al: The evaluation of tumour-infiltrating lymphocytes (TILs) in breast cancer: Recommendations by an International TILs working group 2014. Ann Oncol. 26:259–271. 2015.PubMed/NCBI View Article : Google Scholar
19	Galon J, Pagès F, Marincola FM, Angell HK, Thurin M, Lugli A, Zlobec I, Berger A, Bifulco C, Botti G, et al: Cancer classification using the Immunoscore: A worldwide task force. J Transl Med. 10(205)2012.PubMed/NCBI View Article : Google Scholar
20	Mlecnik B, Tosolini M, Kirilovsky A, Berger A, Bindea G, Meatchi T, Bruneval P, Trajanoski Z, Fridman WH, Pagès F and Galon J: Histopathologic-based prognostic factors of colorectal cancers are associated with the state of the local immune reaction. J Clin Oncol. 29:610–618. 2011.PubMed/NCBI View Article : Google Scholar
21	Lam M, Tie J, Lee B, Desai J, Gibbs P and Tran B: Systemic inflammation-impact on tumor biology and outcomes in colorectal cancer. J Clin Cell Immunol. 6(377)2015.
22	Park JH, Powell AG, Roxburgh CS, Horgan PG, McMillan DC and Edwards J: Mismatch repair status in patients with primary operable colorectal cancer: Associations with the local and systemic tumour environment. Br J Cancer. 114:562–570. 2016.PubMed/NCBI View Article : Google Scholar
23	Mori K, Toiyama Y, Saigusa S, Fujikawa H, Hiro J, Kobayashi M, Ohi M, Araki T, Inoue Y, Tanaka K, et al: Systemic analysis of predictive biomarkers for recurrence in colorectal cancer patients treated with curative surgery. Dig Dis Sci. 60:2477–2487. 2015.PubMed/NCBI View Article : Google Scholar
24	Turner N, Wong HL, Templeton A, Tripathy S, Whiti Rogers T, Croxford M, Jones I, Sinnathamby M, Desai J, Tie J, et al: Analysis of local chronic inflammatory cell infiltrate combined with systemic inflammation improves prognostication in stage II colon cancer independent of standard clinicopathologic criteria. Int J Cancer. 138:671–678. 2016.PubMed/NCBI View Article : Google Scholar
25	Wu B, Zhao S, Sheng Y, Ren L and Song G: The prognostic value of combining the CD8⁺ lymphocyte density and the circulating lymphocyte ratio in circumferential resection margin biopsy in rectal cancer. Medicine (Baltimore). 97(e11972)2018.PubMed/NCBI View Article : Google Scholar
26	Xiao B, Peng J, Zhang R, Xu J, Wang Y, Fang Y, Lin J, Pan Z and Wu X: Density of CD8+ lymphocytes in biopsy samples combined with the circulating lymphocyte ratio predicts pathologic complete response to chemoradiotherapy for rectal cancer. Cancer Manag Res. 9:701–708. 2017.PubMed/NCBI View Article : Google Scholar
27	Afghahi A, Purington N, Han SS, Desai M, Pierson E, Mathur MB, Seto T, Thompson CA, Rigdon J, Telli ML, et al: Higher absolute lymphocyte counts predict lower mortality from early-stage triple-negative breast cancer. Clin Cancer Res. 24:2851–2858. 2018.PubMed/NCBI View Article : Google Scholar
28	Lee KH, Kim EY, Yun JS, Park YL, Do SI, Chae SW and Park CH: The prognostic and predictive value of tumor-infiltrating lymphocytes and hematologic parameters in patients with breast cancer. BMC Cancer. 18(938)2018.PubMed/NCBI View Article : Google Scholar