Prognostic value of tumor-infiltrating T-lymphocytes density in the therapeutic response to initial platinum-based chemotherapy in patients with non-small cell lung cancer

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  • Lora Novaković Lacković University of Banja Luka, Faculty of Medicine, Banja Luka, Republic of Srpska, Bosnia and Herzegovina
  • Ljilja Tadić Latinović University of Banja Luka, Faculty of Medicine, Banja Luka, Republic of Srpska, Bosnia and Herzegovina
  • Mirko Stanetić University of Banja Luka, Faculty of Medicine, Banja Luka, Republic of Srpska, Bosnia and Herzegovina
  • Marko Lacković University Clinical Center of the Republic of Srpska, Internal Clinic, Banja Luka, Republic of Srpska, Bosnia and Herzegovina
Keywords: carcinoma, non-small cell lung, cd4-positive t-lymphocytes, prognosis, t-lymphocytes, t-lymphocytes, cytotoxic, treatment outcome

Abstract


Background/Aim. The fact that lung carcinomas, like other solid tumors, can be immunogenic may have a substantial prognostic value in non-small cell lung cancer (NSCLC). Specific cytotoxic T-lymphocytes (CTL) can be demonstrated in most patients with primary tumors of different histological types. Two main groups of T-lymphocytes participate in the coupled recognition of tumor-specific antigens – CTL (CD8+) and helper T-lymphocytes (CD4+). The aim of the study was to assess the relationship between the tumor infiltration of T-lymphocytes and the therapeutic response to initial chemotherapy. Methods. Data were obtained from patients with NSCLC whose therapeutic response after four cycles of initial platinum-based chemotherapy was observed in relation to the density of tumor-infiltrating T-lymphocytes (CD4+ and CD8+) in small tumor biopsy samples. The therapeutic response was assessed in line with Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 therapeutic response evaluation system. Based on the expected therapeutic response, the patients were divided into three groups: favorable therapeutic response patients (complete and partial regression), stable disease patients, and disease progression patients. To assess the density of CD4+ and CD8+ T-lymphocytes, the number of lymphocytes was determined at ×200 magnification (1.1 mm2). Three visual fields with the densest lymphocyte infiltrate were selected for counting, and the values of all individual fields were added up. Based on the mean value, the samples were classified into the following groups: score 0, score 1, score 2, and score 3. During statistical data processing, low infiltration density combined score 0 and score 1 groups, and high infiltration density combined score 2 and score 3 groups. Based on the collected data, a database was created in SPSS 22.0 software and used for further statistical analysis. Statistical analysis of the data included descriptive and analytical statistics methods. Results. There was no significant difference in the distribution of CD4+ T-lymphocytes and CD8+ T-lymphocytes in the epithelial component of the tumor between patients with a different therapeutic response (χ2 = 2.977; p = 0.226 and χ= 1.329; = 0.515, respectively). There was no significant influence of the infiltration density of CD4+ T-lymphocytes and CD8+ T-lymphocytes in the stromal component of the tumor on the therapeutic response (χ2 = 0.606; p = 0.739 and χ2 = 5.167; p = 0.076, respectively). Conclusion. The research did not prove that patients with a high level of tumor-infiltrating CD4+ and CD8+ T-lymphocytes in the epithelial and stromal component of the NSCLC had a better therapeutic response to standard initial chemotherapy.

References

1.      International Agency for Research on Cancer – World Health Organization. Cancer Over Time – Age-standardized rate (World) per 100 000, incidence, males and females [Internet]. Lyon, FR: International Agency for Research on Cancer; 2016 [accessed 2023 May 22]. Available from: https://gco.
/>iarc.fr/overtime/en/dataviz/trends?populations=75200&multiple_populations=1&sexes=1_2

2.      Bunn PA Jr, Kelly K. New combinations in the treatment of lung cancer: a time for optimism. Chest 2000; 117(4 Suppl 1): 138S–143S.

3.      Bunn PA Jr. Chemotherapy for advanced non-small-cell lung cancer: who, what, when, why? J Clin Oncol 2002; 20(18 Suppl): 23S–33S.

4.      American Cancer Society. Lung Cancer – Early Detection, Diagnosis, and Staging [Internet]. Atlanta, GA: American Cancer Society; 2019 [updated 2023 March 1; accessed 2023 May 18]. Available from: https://www.cancer.org/content/dam/
/>CRC/PDF/Public/8705.00.pdf

5.      Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018; 68(6): 394–424.

6.      Uramoto H, Tanaka F. Recurrence after surgery in patients with NSCLC. Transl Lung Cancer Res 2014; 3(4): 242–9.

7.      Mazieres J, Drilon A, Lusque A, Mhanna L, Cortot AB, Mezquita L, et al. Immune checkpoint inhibitors for patients with advanced lung cancer and oncogenic driver alterations: results from the IMMUNOTARGET registry. Ann Oncol 2019; 30(8): 1321–8.

8.      Chen DS, Mellman I. Oncology Meets Immunology: The Cancer-Immunity Cycle. Immunity 2013; 39(1): 1–10.

9.      Ganesan AP, Johansson M, Ruffell B, Yagui-Beltrán A, Lau J, Jablons DM, et al. Tumor-infiltrating regulatory T cells inhibit endogenous cytotoxic T cell responses to lung adenocarcinoma. J Immunol 2013; 191(4): 2009–17.

10.   Ishibashi Y, Tanaka S, Tajima K, Yoshida T, Kuwano H. Expression of Foxp3 in non-small cell lung cancer patients is significantly higher in tumor tissues than in normal tissues, especially in tumors smaller than 30 mm. Oncol Rep 2006; 15(5): 1315–9.

11.   Fridman WH, Pagès F, Sautès-Fridman C, Galon J. The immune contexture in human tumours: impact on clinical outcome. Nat Rev Cancer 2012; 12(4): 298–306.

12.   Galon J, Pagès F, Marincola FM, Angell HK, Thurin M, Lugli A, et al. Cancer classification using the Immunoscore: a worldwide task force. J Transl Med 2012; 10: 205.

13.   Donnem T, Kilvaer TK, Andersen S, Richardsen E, Paulsen EE, Hald SM, et al. Strategies for clinical implementation of TNM-Immunoscore in resected nonsmall-cell lung cancer. Ann Oncol 2016; 27(2): 225–32.

14.   Hanna N, Johnson D, Termin S, Baker S Jr, Brahmer J, Ellis PM, et al. Systemic therapy for stage IV non-small-cell lung cancer: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol 2017; 35(30): 3484–515.

15.   Pirker R, Filipits M. Adjuvant Therapy in Patients With Completely Resected Non-small-cell Lung Cancer: Current Status and Perspectives. Clin Lung Cancer 2019; 20(1): 1–6.

16.   Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J, et al. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med 2002; 346(2): 92–8.

17.   Baggstrom MQ, Stinchcombe TE, Fried DB, Poole C, Hensing TA, Socinski MA. Third-generation chemotherapy agents in the treatment of advanced non-small cell lung cancer: a meta-analysis. J Thorac Oncol 2007; 2(9): 845–53.

18.   Bindea G, Mlecnik B, Tosolini M, Kirilovsky A, Waldner M, Obenauf AC, et al. Spatiotemporal dynamics of intratumoral immune cells reveal the immune landscape in human cancer. Immunity 2013; 39(4): 782–95.

19.   Dunn GP, Old LJ, Schreiber RD. The immunobiology of cancer immunosurveillance and immunoediting. Immunity 2004; 21(2): 137–48.

20.   Dieu-Nosjean MC, Antoine M, Danel C, Heudes D, Wislez M, Poulot V, et al. Long-term survival for patients with non-small-cell lung cancer with intratumoral lymphoid structures. J Clin Oncol 2008; 26(27): 4410–7.

21.   Brambilla E, Le Teuff G, Marguet S, Lantuejoul S, Dunant A, Graziano S, et al. Prognostic Effect of Tumor Lymphocytic Infiltration in Resectable Non-Small-Cell Lung Cancer. J Clin Oncol 2016; 34(11): 1223–30.

22.   Gooden MJ, de Bock GH, Leffers N, Daemen T, Nijman HW. The prognostic influence of tumour-infiltrating lymphocytes in cancer: a systematic review with meta-analysis. Br J Cancer 2011; 105(1): 93–103.

23.   Liu H, Zhang T, Ye J, Li H, Huang J, Li X, et al. Tumor-infiltrating lymphocytes predict response to chemotherapy in patients with advance non-small cell lung cancer. Cancer Immunol Immunother 2012; 61(10): 1849–56.

24.   Nakamura H, Saji H, Ogata A, Hosaka M, Hagiwara M, Kawasaki N, et al. Immunologic parameters as significant prognostic factors in lung cancer. Lung Cancer 2002; 37(2): 161–9.

25.   Hiraoka K, Miyamoto M, Cho Y, Suzuoki M, Oshikiri T, Nakakubo Y, et al. Concurrent infiltration by CD8+ T cells and CD4+ T cells is a favourable prognostic factor in non-small-cell lung carcinoma. Br J Cancer 2006; 94(2): 275–80.

26.   Jackute J, Zemaitis M, Pranys D, Sitkauskiene B, Miliauskas S, Bajoriunas V, et al. The prognostic influence of tumor infiltrating Foxp3(+)CD4(+), CD4(+) and CD8(+) T cells in resected non-small cell lung cancer. J Inflamm (Lond) 2015; 12: 63.

27.   Schalper KA, Brown J, Carvajal-Hausdorf D, McLaughlin J, Velcheti V, Syrigos KN, et al. Objective measurement and clinical significance of TILs in non-small cell lung cancer. J Natl Cancer Inst 2015; 107(3): dju435.

28.   Dobrzanski MJ, Reome JB, Hylind JC, Rewers-Felkins KA. CD8-mediated type 1 antitumor responses selectively modulate endogenous differentiated and nondifferentiated T cell localization, activation, and function in progressive breast cancer. J Immunol 2006; 177(11): 8191–201.

29.   Kawai O, Ishii G, Kubota K, Murata Y, Naito Y, Mizuno T, et al. Predominant Infiltration of Macrophages and CD8+T Cells in Cancer Nests Is a Significant Predictor of Survival in Stage IV Nonsmall Cell Lung Cancer. Cancer 2008; 113(6): 1387–95.

30.   Kirshberg S, Izhar U, Amir G, Demma J, Vernea F, Beider K, et al. Involvement of CCR6/CCL20/IL-17 axis in NSCLC disease progression. PLoS One 2011; 6: e24856.

31.   Salih HR, Rammensee HG, Steinle A. Cutting edge: down-regulation of MICA on human tumors by proteolytic shedding. J Immunol 2002; 169(8): 4098–102.

32.   Wald O, Shapira OM, Izhar U. CXCR4/CXCL12 axis in non small cell lung cancer (NSCLC) pathologic roles and therapeutic potential. Theranostics 2013; 3(1): 26–33.

33.   Kataki A, Scheid P, Piet M, Marie B, Martinet N, Martinet Y, et al. Tumor infiltrating lymphocytes and macrophages have a potential dual role in lung cancer by supporting both host-defense and tumor progression. J Lab Clin Med 2002; 140(5): 320–8.

34.   Obeid JM, Wages NA, Hu Y, Deacon DH, Slingluff CL Jr. Heterogeneity of CD8+ tumor-infiltrating lymphocytes in non-small-cell lung cancer: impact on patient prognostic assessments and comparison of quantification by different sampling strategies. Cancer Immunol Immunother 2017; 66(1): 33–43.

Published
2023/09/29
Section
Original Paper