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A Novel Prognostic Assessment of an Anti-tumor Biomarker: An In Silico Analysis of Tumor Infiltrating Lymphocytes in Melanoma

 


Abstract: Tumor infiltrating lymphocytes (TILs) are adaptive immune cells that play a significant role in engulfing mutated cells in the body's antitumor response. However, due to a lack of TIL analysis softwares, oncologists have not yet identified whether TILs are a viable prognostic biomarker for cancers. They instead have continued to create prognoses based on the obsolete method of measuring the depth of a patient’s cancer. Thus, this novel In Silico study analyzed the impact of varying TIL concentrations on the clinical outcomes of melanoma patients using open-source digital image analysis (DIA) software. I utilized the tumor images and clinical data of 48 melanoma patients, as melanoma is the most severe form of skin cancer, impacting 57,000 people annually, for data analyses. Using cell classification features with novel classification code and Qupath DIA software, I examined the concentrations of TILs, in the context of tumor cells and stroma, of each melanoma patient. I found that patients with high TIL concentrations had a significantly higher mean disease-free survival rate of 100% compared to the 50% mean disease-free survival rate of patients with low TIL concentrations (p<0.05). Additionally, patients who had one or more melanoma recurrence had significantly lower TIL concentrations than those who did not (p<0.005). These novel results suggest that TILs are highly prognostic of melanoma patients’ clinical outcomes and may be utilized in a melanoma treatment administration framework. Future research may expand on this study by exploring which specific TILs have the greatest prognostic significance.


References

  1. Acs, B., Ahmed, F. S., Gupta, S., Wong, P. F., Gartrell, R. D., Sarin Pradhan, J., Rizk, E. M., Gould Rothberg, B., Saenger, Y. M., & Rimm, D. L. (2019). An open source automated tumor infiltrating lymphocyte algorithm for prognosis in melanoma. Nature communications, 10(1), 5440. https://doi.org/10.1038/s41467-019-13043-2

  2. Huang, H., Nie, C. P., Liu, X. F., Song, B., Yue, J. H., Xu, J. X., He, J., Li, K., Feng, Y. L., Wan, T., Zheng, M., Zhang, Y. N., Ye, W. J., Li, J. D., Li, Y. F., Li, J. Y., Cao, X. P., Liu, Z. M., Zhang, X. S., Liu, Q., Li, J. (2022). Phase I study of adjuvant immunotherapy with autologous tumor-infiltrating lymphocytes in locally advanced cervical cancer. The Journal of clinical investigation, 132(15), e157726. https://doi.org/10.1172/JCI157726\

  3. Hu, B., Sun, M., Wang, Z., Zheng, Y., Cai, W., Shi, H. H., Zhuang, Y., & Lin, Q. (2020). Prognostic Value of Programmed Cell Death-Ligand 1 Expression in Tumor-Infiltrating Lymphocytes and Viral Load in Peripheral Blood Mononuclear Cells for Epstein-Barr Virus-Positive Nasopharyngeal Carcinoma. Oxford Academic, 66(9), 1219–1227. https://doi.org/10.1093/clinchem/hvaa170Bonilla, F. A., & Oettgen, H. C. (2010). Adaptive immunity. The Journal of Allergy and Clinical Immunology, 125(2 Suppl 2), S33–S40. https://doi.org/10.1016/j.jaci.2009.09.017

  4. Maibach, F., Sadozai, H., Seyed Jafari, S. M., Hunger, R. E., & Schenk, M. (2020). Tumor-infiltrating lymphocytes and their prognostic value in cutaneous melanoma. Frontiers in Immunology, 11, 2105. https://doi.org/10.3389/fimmu.2020.02105

  5. Paijens, S. T., Vledder, A., de Bruyn, M., & Nijman, H. W. (2021). Tumor-infiltrating lymphocytes in the immunotherapy era. Pharmacol Ther., 221(4), 107753. https://doi.org/10.1038/s41423-020-00565-9

  6. Engelhard, V., Conejo-Garcia, J. R., Ahmed, R., Nelson, B. H., Willard-Gallo, K., Bruno, T. C., & Fridman, W. H. (2021). B cells and cancer. Cancer Cell, 39(10), 1293–1296. https://doi.org/10.1016/j.ccell.2021.09.007

  7. Hirai, I., Funakoshi, T., Kamijuku, H., Fukuda, K., Mori, M., Sakurai, M., Koda, Y., Kato, J., Mori, T., Watanabe, N., Noji, S., Yaguchi, T., Iwata, T., Ohta, S., Fujita, T., Tanosaki, R., Handa, M., Okamoto, S., Amagai, M., & Kawakami, Y. (2021). Adoptive cell therapy using tumor-infiltrating lymphocytes for melanoma refractory to immune-checkpoint inhibitors. Cancer Science, 112(8), 3163–3172. https://doi.org/10.1111/cas.15009

  8. Sheth, M., & Ko, J. (2021). Exploring the relationship between Overall Survival (OS), Progression free survival (PFS) and objective response rate (ORR) in patients with advanced melanoma. Cancer Treatment and Research Communications, 26, 100272. https://doi.org/10.1016/j.ctarc.2020.100272

  9. Xiao, Y., & Yu, D. (2021). Tumor microenvironment as a therapeutic target in cancer.Nature communications, 13(4), 203-210. https://doi.org/10.1016/j.pharmthera.2020.107753

  10. Suzuki, H., Kawasaki, Y., Miura, M., Hatakeyama, H., Shina, K., Suzuki, S., Yamada, T., Suzuki, M., Ito, A., & Omori, Y. (2022). Tumor infiltrating lymphocytes are prognostic factors and can be markers of sensitivity to chemoradiotherapy in head and neck squamous cell carcinoma. Asian Pacific Journal of Cancer Prevention: APJCP, 23(4), 1271–1278. https://doi.org/10.31557/APJCP.2022.23.4.1271\

  11. Stevanović, S., Helman, S. R., Wunderlich, J. R., Langhan, M. M., Doran, S. L., Kwong, M. L. M., Somerville, R. P. T., Klebanoff, C. A., Kammula, U. S., Sherry, R. M., Yang, J. C., Rosenberg, S. A., & Hinrichs, C. S. (2019). A phase II study of tumor-infiltrating lymphocyte therapy for human papillomavirus-associated epithelial cancers. Clinical Cancer Research : An Official Journal of the American Association for Cancer Research, 25(5), 1486–1493. https://doi.org/10.1158/1078-0432.CCR-18-2722

  12. Chesney, J., Lewis, K. D., Kluger, H., Hamid, O., Whitman, E., Thomas, S., Wermke, M., Cusnir, M., Domingo-Musibay, E., Phan, G. Q., Kirkwood, J. M., Hassel, J. C., Orloff, M., Larkin, J., Weber, J., Furness, A. J. S., Khushalani, N. I., Medina, T., Egger, M. E., Graf Finckenstein, F., Sarnaik, A. (2022). Efficacy and safety of lifileucel, a one-time autologous tumor-infiltrating lymphocyte (TIL) cell therapy, in patients with advanced melanoma after progression on immune checkpoint inhibitors and targeted therapies: Pooled analysis of consecutive cohorts of the C-144-01 study. Journal for Immunotherapy of Cancer, 10(12), e005755. https://doi.org/10.1136/jitc-2022-005755

  13. Abe, N., Matsumoto, H., Takamatsu, R., Tamaki, K., Takigami, N., Uehara, K., Kamada, Y., Tamaki, N., Motonari, T., Unesoko, M., Nakada, N., Zaha, H., & Yoshimi, N. (2020). Quantitative digital image analysis of tumor-infiltrating lymphocytes in HER2-positive breast cancer. Virchows, 476(5), 701–709. https://doi.org/10.1007/s00428-019-02730-6

  14. Gao, F., Xie, K., Xiang, Q., Qin, Y., Chen, P., Wan, H., Deng, Y., Huang, J., & Wu, H. (2021). The density of tumor-infiltrating lymphocytes and prognosis in resectable hepatocellular carcinoma: A two-phase study. Aging, 13(7), 9665–9678. https://doi.org/10.18632/aging.202710

  15. Koelzer, V. H., Gisler, A., Hanhart, J. C., Griss, J., Wagner, S. N., Willi, N., Cathomas, G., Sachs, M., Kempf, W., Thommen, D. S., & Mertz, K. D. (2018). Digital image analysis improves precision of PD-L1 scoring in cutaneous melanoma. Histopathology, 73(3), 397–406. https://doi.org/10.1111/his.13528

  16. Grinberg-Bleyer, Y., Caron, R., Seeley, J. J., De Silva, N. S., Schindler, C. W., Hayden, M. S., Klein, U., & Ghosh, S. (2018). The Alternative NF-κB Pathway in Regulatory T Cell Homeostasis and Suppressive Function. The Journal of Immunology, 200(7), 2362–2371. https://doi.org/10.4049/jimmunol.1800042

  17. Disis M. L. (2010). Immune regulation of cancer. Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology, 28(29), 4531–4538. https://doi.org/10.1200/JCO.2009.27.2146

  18. Creelan, B. C., Wang, C., Teer, J. K., Toloza, E. M., Yao, J., Kim, S., Landin, A. M., Mullinax, J. E., Saller, J. J., Saltos, A. N., Noyes, D. R., Montoya, L. B., Curry, W., Pilon-Thomas, S. A., Chiappori, A. A., Tanvetyanon, T., Kaye, F. J., Thompson, Z. J., Yoder, S. J., Fang, B., Antonia, S. J. (2021). Tumor-infiltrating lymphocyte treatment for anti-PD-1-resistant metastatic lung cancer: a phase 1 trial. Nature Medicine, 27(8), 1410–1418. https://doi.org/10.1038/s41591-021-01462-y

  19. Sambi, M., Bagheri, L., & Szewczuk, M. R. (2019). Current Challenges in Cancer Immunotherapy: Multimodal Approaches to Improve Efficacy and Patient Response Rates. Journal of oncology, 2019, 4508794. https://doi.org/10.1155/2019/4508794

  20. Sun, L., Wang, X., Saredy, J., Yuan, Z., Yang, X., & Wang, H. (2020). Innate-adaptive immunity interplay and redox regulation in immune response. Redox Biology, 37, 101759. https://doi.org/10.1016/j.redox.2020.101759

  21. Vesely, M. D., Kershaw, M. H., Schreiber, R. D., & Smyth, M. J. (2011). Natural innate and adaptive immunity to cancer. Annual Review of Immunology, 29, 235–271. https://doi.org/10.1146/annurev-immunol-031210-101324

  22. Wolchok, J. D., Chiarion-Sileni, V., Gonzalez, R., Grob, J. J., Rutkowski, P., Lao, C. D., Cowey, C. L., Schadendorf, D., Wagstaff, J., Dummer, R., Ferrucci, P. F., Smylie, M., Butler, M. O., Hill, A., Márquez-Rodas, I., Haanen, J. B. A. G., Guidoboni, M., Maio, M., Schöffski, P., Carlino, M. S.,  Hodi, F. S. (2022). Long-term outcomes with nivolumab plus ipilimumab or nivolumab alone versus ipilimumab in patients with ]advanced melanoma. Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology, 40(2), 127–137. https://doi.org/10.1200/JCO.21.02229

  23. Kristan, M. M., Toro-Tobon, D., Francis, N., Desale, S., Bikas, A., Jonklaas, J., & Goyal, R. M. (2022). Immunotherapy-associated hypothyroidism: comparison of the pre-existing with de-novo hypothyroidism. Frontiers in Endocrinology, 13, 798253. https://doi.org/10.3389/fendo.2022.798253