Intra‐tumoral tumor infiltrating Lymphocyte‐T CD8+ and chemotherapy response in colorectal cancer: A prospective observational study

Deny Budiman, Kiki Lukman, Reno Rudiman, Bambang Am Am Setya Sulthana, Yunia Sribudiani, Prapanca Nugraha, Lisa Y. Hasibuan, Birgitta M. Dewayani

Article ID: 2815
Vol 8, Issue 1, 2024

VIEWS - 538 (Abstract) 183 (PDF)


Background: The immunotherapy approach to colorectal cancer is becoming one of the key approaches to colorectal cancer treatment. One of the components of immune responses is tumor‐infiltrating lymphocyte CD8+ cells (TILs CD8+). While chemotherapy is one of the main treatments for colorectal cancer, we need to consider immunotherapy for advanced colorectal cancer. Thus, this study is aimed at finding the association between TIL CD8+ expression and chemotherapy response. Methods: This is a prospective cohort study with colorectal cancer patients in the Digestive Surgery division of a tertiary general hospital in West Java, Indonesia. An immunohistochemistry examination was used to evaluate the expression of TIL CD8+. The response evaluation criteria in solid tumors (RECIST) were used for the evaluation of chemotherapy response. Results: There were 53 research subjects included. There were 20 (37.7%) subjects with high expression of TILs CD8+; there were 30 (56.6%) subjects in stage III, followed by stage IV (17.32%) and stage II (6.11%). There were 18 subjects (34%) who showed progressive disease, 17 subjects (32.1%) showed partial response, and 16 subjects (30.2%) with high expression of TILs CD8+ showed partial chemotherapy response. The TILs CD8+ expression showed no significant relationship with age, sex, subtype, grade, or tumor location, but showed a significant relationship with stage and chemotherapy response (P < 0.05). Conclusion: High TILs CD8+ expression show a relationship with better chemotherapy response and a better prognosis based on disease stage in colorectal cancer patients.


chemotherapy; colorectal cancer; immunohistochemistry; infiltrating lymphocytes; tumor‐infiltrating lymphocytes

Full Text:



1. Jalilian H, Ziaei M, Weiderpass E, et al. Cancer incidence and mortality among firefighters. International Journal of Cancer 2019; 145(10): 2639–2646. doi: 10.1002/ijc.32199

2. Pedersen JK, Rosholm JU, Ewertz M, et al. Declining cancer incidence at the oldest ages: Hallmark of aging or lower diagnostic activity? Journal of Geriatric Oncology 2019; 10(5): 792–798. doi: 10.1016/j.jgo.2019.02.001

3. Célind J, Ohlsson C, Bygdell M, et al. Childhood body mass index is associated with risk of adult colon cancer in men: An association modulated by pubertal change in body mass index. Cancer Epidemiology, Biomarkers & Prevention: A Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology 2019; 28(5): 974–979. doi: 10.1158/1055-9965.EPI-18-1077

4. Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: a cancer journal for clinicians. 2021; 71(3): 209-249. doi: 10.3322/caac.21660

5. Dulskas A, Gaizauskas V, Kildusiene I, et al. Improvement of survival over time for colorectal cancer patients: A population-based study. Journal of Clinical Medicine 2020; 9(12): 4038. doi: 10.3390/jcm9124038

6. Dahlin AM, Henriksson ML, Van Guelpen B, et al. Colorectal cancer prognosis depends on T-cell infiltration and molecular characteristics of the tumor. Modern Pathology 2011; 24(5): 671–682. doi: 10.1038/modpathol.2010.234

7. Salama P, Phillips M, Grieu F, et al. Tumor-infiltrating FOXP3+ T regulatory cells show strong prognostic significance in colorectal cancer. Journal of Clinical Oncology 2009; 27(2): 186–192. doi: 10.1200/jco.2008.18.7229

8. Nosho K, Baba Y, Tanaka N, et al. Tumour‐infiltrating T‐cell subsets, molecular changes in colorectal cancer, and prognosis: Cohort study and literature review. The Journal of Pathology 2010; 222(4): 350–366. doi: 10.1002/path.2774

9. Mlecnik B, Tosolini M, Kirilovsky A, et al. Histopathologic-based prognostic factors of colorectal cancers are associated with the state of the local immune reaction. Journal of Clinical Oncology 2011; 29(6): 610–618. doi: 10.1200/jco.2010.30.5425

10. Zhang N, Bevan MJ. CD8+ T cells: Foot soldiers of the immune system. Immunity 2011; 35(2): 161–168. doi: 10.1016/j.immuni.2011.07.010

11. Pagès F, Berger A, Camus M, et al. Effector memory T cells, early metastasis, and survival in colorectal cancer. The New England Journal of Medicine 2005; 353(25): 2654–2666. doi: 10.1056/NEJMoa051424

12. Jochems C, Schlom J. Tumor-infiltrating immune cells and prognosis: The potential link between conventional cancer therapy and immunity. Experimental Biology and Medicine 2011; 236(5): 567–579. doi: 10.1258/ebm.2011.011007

13. Senovilla L, Vacchelli E, Galon J, et al. Trial watch: Prognostic and predictive value of the immune infiltrate in cancer. OncoImmunology 2012; 1(8): 1323–1343. doi: 10.4161/onci.22009

14. Slaney CY, Kershaw MH, Darcy PK. Trafficking of T cells into tumors. Cancer Research 2014; 74(24): 7168–7174. doi: 10.1158/0008-5472.can-14-2458

15. Floc’h AL, Jalil A, Vergnon I, et al. αEβ7 integrin interaction with E-cadherin promotes antitumor CTL activity by triggering lytic granule polarization and exocytosis. The Journal of Experimental Medicine 2007; 204(3): 559–570. doi: 10.1084/jem.20061524

16. Anikeeva N, Somersalo K, Sims TN, et al. Distinct role of lymphocyte function-associated antigen-1 in mediating effective cytolytic activity by cytotoxic T lymphocytes. Proceedings of the National Academy of Sciences of the United States of America 2005; 102(18): 6437–6442. doi: 10.1073/pnas.0502467102

17. Huh JW, Lee JH, Kim HR. Prognostic significance of tumor-infiltrating lymphocytes for patients with colorectal cancer. Archives of Surgery 2012; 147(4): 366–372. doi: 10.1001/archsurg.2012.35

18. Morris M, Platell C, Iacopetta B. Tumor-infiltrating lymphocytes and perforation in colon cancer predict positive response to 5-fluorouracil chemotherapy. Clinical Cancer Research 2008; 14(5): 1413–1417. doi: 10.1158/1078-0432.ccr-07-1994

19. Prall F, Dührkop T, Weirich V, et al. Prognostic role of CD8+ tumor-infiltrating lymphocytes in stage III colorectal cancer with and without microsatellite instability. Human Pathology 2004; 35(7): 808–816. doi: 10.1016/j.humpath.2004.01.022

20. Rudiman R. A Comprehensive Approach to Colorectal Cancer (Indonesian). Jakad Media Publishing; 2023.

21. Cuschieri S. The STROBE guidelines. Saudi Journal of Anaesthesia 2019; 13(Suppl 1): S31–S34. doi: 10.4103/sja.SJA_543_18

22. Irawan E, Lukman K, Usman N, et al. Identification of tumor infiltrating lymphocyte CD8 in Indonesian colorectal cancer population: A cross-sectional study. Bali Medical Journal 2023; 12(2): 1781–1785. doi: 10.15562/bmj.v12i2.4520

23. Cheeseman SL, Joel SP, Chester JD, et al. A ‘modified de Gramont’ regimen of fluorouracil, alone and with oxaliplatin, for advanced colorectal cancer. British Journal of Cancer 2002; 87(4): 393–399. doi: 10.1038/sj.bjc.6600467

24. Leicher LW, de Graaf JC, Coers W, et al. Tolerability of capecitabine monotherapy in metastatic colorectal cancer: A real-world study. Drugs in R&D 2016; 17(1): 117–124. doi: 10.1007/s40268-016-0154-8

25. Choi JH, Ahn MJ, Rhim HC, et al. Comparison of WHO and RECIST criteria for response in metastatic colorectal carcinoma. Cancer Research and Treatment 2005; 37(5): 290–293. doi: 10.4143/crt.2005.37.5.290

26. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). European Journal of Cancer 2009; 45(2): 228–247. doi: 10.1016/j.ejca.2008.10.026

27. Mármol I, Sánchez-de-Diego C, Pradilla Dieste A, et al. Colorectal carcinoma: A general overview and future perspectives in colorectal cancer. International Journal of Molecular Sciences 2017; 18(1): 197. doi: 10.3390/ijms18010197

28. American Cancer Society. What is colorectal cancer? Available online: (accessed on 30 April 2023).

29. Lotfollahzadeh S, Recio-Boiles A, Cagir B. Colon cancer. Available online: (accessed on 6 January 2023).

30. Recio-Boiles A, Kashyap S, Tsoris A, et al. Rectal cancer. Available online: (accessed on 6 January 2023).

31. Abancens M, Bustos V, Harvey H, et al. Sexual dimorphism in colon cancer. Frontiers in Oncology 2020; 10: 607909. doi: 10.3389/fonc.2020.607909

32. Fleming M, Ravula S, Tatishchev SF, Wang HL. Colorectal carcinoma: Pathologic aspects. Journal of Gastrointestinal Oncology 2012; 3(3): 153–173. doi: 10.3978/j.issn.2078-6891.2012.030

33. American Cancer Society. Colorectal cancer facts & figures 2014–2016. Available online: file:///C:/Users/EDY/Downloads/colorectal-cancer-facts-and-figures-2014-2016.pdf (accessed on 31 October 2023).

34. Sideras K, Galjart B, Vasaturo A, et al. Prognostic value of intra‐tumoral CD8+/FoxP3+ lymphocyte ratio in patients with resected colorectal cancer liver metastasis. Journal of Surgical Oncology 2018; 118(1): 68–76. doi: 10.1002/jso.25091

35. Trabelsi M, Farah F, Zouari B, et al. An immunoscore system based on CD3+ and CD8+ infiltrating lymphocytes densities to predict the outcome of patients with colorectal adenocarcinoma. OncoTargets and Therapy 2019; 12: 8663–8673. doi: 10.2147/OTT.S211048

36. Guan Y, Kraus SG, Quaney MJ, et al. FOLFOX chemotherapy ameliorates CD8 T lymphocyte exhaustion and enhances checkpoint blockade efficacy in colorectal cancer. Frontiers in Oncology 2020; 10: 586. doi: 10.3389/fonc.2020.00586

37. Alsalman A, Al-Mterin MA, Murshed K, et al. Circulating and tumor-infiltrating immune checkpoint-expressing CD8+ Treg/T cell subsets and their associations with disease-free survival in colorectal cancer patients. Cancers 2022; 14(13): 3194. doi: 10.3390/cancers14133194

38. Xin H, Zhou C, Wang G, et al. Heterogeneity of PD-L1 expression and CD8 lymphocyte infiltration in metastatic colorectal cancer and their prognostic significance. Heliyon 2023; 9(2): e13048. doi: 10.1016/j.heliyon.2023.e13048

39. Seo AN, Lee HJ, Kim EJ, et al. Tumour-infiltrating CD8+ lymphocytes as an independent predictive factor for pathological complete response to primary systemic therapy in breast cancer. British Journal of Cancer 2013; 109(10): 2705–2713. doi: 10.1038/bjc.2013.634

40. Rudiman R, Wijaya A, Sribudiani Y, et al. Identification of KRAS mutation and HER2 expression in Indonesian colorectal cancer population: A cross-sectional study. Annals of Medicine & Surgery 2023; 85(5): 1761–1768. doi: 10.1097/MS9.0000000000000694

41. Lukman K, Reza AT, Hasibuan LY, et al. Different clinicopathological characteristics in indonesian colorectal patients with NRAS mutations and HER2 over-expression. Asian Pacific Journal of Cancer Prevention 2023; 24(4): 1373–1377. doi: 10.31557/APJCP.2023.24.4.1373

42. Purnama A, Lukman K, Ruchimat T, et al. Vitamin D and diagnostic colonoscopy for colorectal cancer in Indonesian population: A cross-sectional study. Open Access Macedonian Journal of Medical Sciences 2023; 11(B): 439–445. doi: 10.3889/oamjms.2023.11561

43. Lukman K, Mulyawan A, Nugrahani AD, et al. The analysis between clinicopathological aspect of early-onset vs. late-onset colorectal cancer and mortality rate: A cross-sectional study. Annals of Medicine and Surgery 2023; 85(6): 2496–2501. doi: 10.1097/MS9.0000000000000757

44. Andreas R, Rudiman R, Lukman K, et al. Different clinicopathological characteristics in Indonesian colorectal patients with RAS mutations and LC3 over-expression: A cross-sectional study. Bali Medical Journal 2023; 12(2): 1774–1780. doi: 10.15562/bmj.v12i2.4519



  • There are currently no refbacks.

Copyright (c) 2024 Deny Budiman, Kiki Lukman, Reno Rudiman, Bambang Am Am Setya Sulthana, Yunia Sribudiani, Prapanca Nugraha, Lisa Y. Hasibuan, Birgitta M. Dewayani

License URL:

This site is licensed under a Creative Commons Attribution 4.0 International License.