The prognostic impact of tumor-infiltrating lymphocytes (TILs) on outcomes and treatment efficacy for patients with melanoma in the contemporary era remains poorly characterized.
Consecutive patients who underwent wide excision and sentinel lymph node biopsy for cutaneous melanoma 1 mm thick or thicker at a single institution were identified (2006–2019). The patients were stratified based on primary tumor TIL status as brisk (bTILs), non-brisk (nbTILs), or absent (aTILs). Associations between patient factors and outcomes were analyzed using multivariable analysis.
Of the 1017 patients evaluated, 846 (83.2 %) had primary TILs [nbTILs (n = 759, 89.7 %) and bTILs (n = 87, 10.3 %)]. In the multivariable analysis, the patients with any type of TILs had higher rates of regression [odds ratio (OR), 1.86; p = 0.016], lower rates of acral lentiginous histology (OR, 0.22; p < 0.001), and lower rates of SLN positivity (OR, 0.64; p = 0.042) than those without TILs. The multivariable analysis found no association between disease-specific survival and bTILs [hazard ratio (HR), 1.04; p = 0.927] or nbTILs (HR, 0.89; p = 0.683). An association was found between bTILs and recurrence-free survival (RFS) advantage [bTILs (HR 0.46; p = 0.047), nbTILs (HR 0.71; p = 0.088)], with 5-year RFS rates of 84 % for bTILs, 71.8 % for nbTILs, and 68.4 % for aTILs (p = 0.044). For the 114 immune checkpoint blockade (ICB)-naïve patients who experienced a recurrence treated with ICB therapy, no association was observed between progression-free survival and bTILs (HR, 0.64; p = 0.482) or nbTILs (HR, 0.58; p = 0.176).
The prognostic significance of primary TILs in the contemporary melanoma era appears complex. Further studies characterizing the phenotype of TILs and their association with regional metastasis and responsiveness to ICB therapy are warranted.
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Amin M, Edge S, Greene F, et al. AJCC Cancer Staging Manual. 8th ed. Springer International Publishing: American Joint Commission on Cancer, Berlin 2017.
Clark WH, Elder DE, Guerry D, et al. Model predicting survival in stage I melanoma based on tumor progression. J Natl Cancer Inst. 1989;81:1893–904. https://doi.org/10.1093/jnci/81.24.1893.
Mandalà M, Imberti GL, Piazzalunga D, et al. Clinical and histopathological risk factors to predict sentinel lymph node positivity, disease-free and overall survival in clinical stages I-II AJCC skin melanoma: outcome analysis from a single-institution prospectively collected database. Eur J Cancer. 2009;45:2537–45. https://doi.org/10.1016/j.ejca.2009.05.034.
Clemente CG, Mihm MC, Bufalino R, Zurrida S, Collini P, Cascinelli N. Prognostic value of tumor-infiltrating lymphocytes in the vertical growth phase of primary cutaneous melanoma. Cancer. 1996;77:1303–10. https://doi.org/10.1002/(SICI)1097-0142(19960401)77:7%3c1303::AID-CNCR12%3e3.0.CO;2-5.
Azimi F, Scolyer RA, Rumcheva P, et al. Tumor-infiltrating lymphocyte grade is an independent predictor of sentinel lymph node status and survival in patients with cutaneous melanoma. J Clin Oncol. 2012;30:2678–83. https://doi.org/10.1200/JCO.2011.37.8539.
Thomas NE, Busam KJ, From L, et al. Tumor-infiltrating lymphocyte grade in primary melanomas is independently associated with melanoma-specific survival in the population-based genes, environment, and melanoma study. J Clin Oncol. 2013;31:4252–9. https://doi.org/10.1200/JCO.2013.51.3002.
Kruper LL, Spitz FR, Czerniecki BJ, et al. Predicting sentinel node status in AJCC stage I/II primary cutaneous melanoma. Cancer. 2006;107:2436–45. https://doi.org/10.1002/cncr.22295.
Burton AL, Roach BA, Mays MP, et al. Prognostic significance of tumor-infiltrating lymphocytes in melanoma. Am Surg. 2011;77:188–92.
Taylor RC, Patel A, Panageas KS, Busam KJ, Brady MS. Tumor-infiltrating lymphocytes predict sentinel lymph node positivity in patients with cutaneous melanoma. J Clin Oncol. 2007;25:869–75. https://doi.org/10.1200/JCO.2006.08.9755.
Barnhill RL, Fine JA, Roush GC, Berwick M. Predicting five-year outcome for patients with cutaneous melanoma in a population-based study. Cancer. 1996;78:427–32. https://doi.org/10.1002/(SICI)1097-0142(19960801)78:3%3c427::AID-CNCR8%3e3.0.CO;2-G.
Yang J, Lian JW, Chin YH, et al. Assessing the prognostic significance of tumor-infiltrating lymphocytes in patients with melanoma using pathologic features identified by natural language processing. JAMA Netw Open. 2021;4:e2126337. https://doi.org/10.1001/jamanetworkopen.2021.26337.
Linette GP, Carreno BM. Tumor-infiltrating lymphocytes in the checkpoint inhibitor era. Curr Hematol Malig Rep. 2019;14:286–91. https://doi.org/10.1007/s11899-019-00523-x.
Zou W, Wolchok JD, Chen L. PD-L1 (B7-H1) and PD-1 pathway blockade for cancer therapy: mechanisms, response biomarkers, and combinations. Sci Transl Med. 2016;8:328rv4. Doi:https://doi.org/10.1126/scitranslmed.aad7118.
Li F, Li C, Cai X, et al. The association between CD8+ tumor-infiltrating lymphocytes and the clinical outcome of cancer immunotherapy: a systematic review and meta-analysis. EclinicalMedicine. 2021;41:101134. https://doi.org/10.1016/j.eclinm.2021.101134.
Klein S, Mauch C, Brinker K, et al. Tumor-infiltrating lymphocyte clusters are associated with response to immune checkpoint inhibition in BRAF V600. Sci Rep. 2021;11:1834. https://doi.org/10.1038/s41598-021-81330-4.
Mihm MC, Mulé JJ. Reflections on the histopathology of tumor-infiltrating lymphocytes in melanoma and the host immune response. Cancer Immunol Res. 2015;3:827–35. https://doi.org/10.1158/2326-6066.CIR-15-0143.
Lemeshow S, Hosmer DW. A review of goodness-of-fit statistics for use in the development of logistic regression models. Am J Epidemiol. 1982;115:92–106. https://doi.org/10.1093/oxfordjournals.aje.a113284.
Lee M, Han J. Statistical methods and models in the analysis of time to event data. Ann Transl Med. Feb 2020;8:73. https://doi.org/10.21037/atm.2019.12.66.
Schemper M, Smith TL. A note on quantifying follow-up in studies of failure time. Control Clin Trials. 1996;17:343–6. https://doi.org/10.1016/0197-2456(96)00075-x.
StataCorp. Stata Statistical Software: Release 17. StataCorp LLC, College Station, TX, 2021.
Egger ME, Gilbert JE, Burton AL, et al. Lymphovascular invasion as a prognostic factor in melanoma. Am Surg. 2011;77:992–7.
Vose BM, Moore M. Human tumor-infiltrating lymphocytes: a marker of host response. Semin Hematol. 1985;22:27–40.
Weiss SA, Han SW, Lui K, et al. Immunologic heterogeneity of tumor-infiltrating lymphocyte composition in primary melanoma. Hum Pathol. 2016;57:116–25. https://doi.org/10.1016/j.humpath.2016.07.008.
Passarelli A, Mannavola F, Stucci LS, Tucci M, Silvestris F. Immune system and melanoma biology: a balance between immunosurveillance and immune escape. Oncotarget. 2017;8:106132–42. https://doi.org/10.18632/oncotarget.22190.
Tod BM, Schneider JW, Bowcock AM, Visser WI, Kotze MJ. The tumor genetics of acral melanoma: what should a dermatologist know? JAAD Int. 2020;1:135–47. https://doi.org/10.1016/j.jdin.2020.07.004.
Aivazian K, Ahmed T, El Sharouni MA, et al. Histological regression in melanoma: impact on sentinel lymph node status and survival. Mod Pathol. 2021;34:1999–2008. https://doi.org/10.1038/s41379-021-00870-2.
Aung PP, Nagarajan P, Prieto VG. Regression in primary cutaneous melanoma: etiopathogenesis and clinical significance. Lab Invest. 2017;97(6):657–668. https://doi.org/10.1038/labinvest.2017.8.
Ribero S, Gualano MR, Osella-Abate S, et al. Association of histologic regression in primary melanoma with sentinel lymph node status: a systematic review and meta-analysis. JAMA Dermatol. 2015;151:1301–7. https://doi.org/10.1001/jamadermatol.2015.2235.
Gualano MR, Osella-Abate S, Scaioli G, et al. Prognostic role of histological regression in primary cutaneous melanoma: a systematic review and meta-analysis. Br J Dermatol. 2018;178:357–62. https://doi.org/10.1111/bjd.15552.
Sinnamon AJ, Sharon CE, Song Y, et al. The prognostic significance of tumor-infiltrating lymphocytes for primary melanoma varies by sex. J Am Acad Dermatol. 2018;79:245–51. https://doi.org/10.1016/j.jaad.2018.02.066.
Fu Q, Chen N, Ge C, et al. Prognostic value of tumor-infiltrating lymphocytes in melanoma: a systematic review and meta-analysis. Oncoimmunology. 2019;2019(8):1593806. https://doi.org/10.1080/2162402X.2019.1593806.
Fortes C, Mastroeni S, Mannooranparampil TJ, et al. Tumor-infiltrating lymphocytes predict cutaneous melanoma survival. Melanoma Res. 2015;25:306–11. https://doi.org/10.1097/CMR.0000000000000164.
Gataa I, Mezquita L, Rossoni C, et al. Tumour-infiltrating lymphocyte density is associated with favourable outcome in patients with advanced non-small cell lung cancer treated with immunotherapy. Eur J Cancer. 2021;145:221–9. https://doi.org/10.1016/j.ejca.2020.10.017.
Wong PF, Wei W, Smithy JW, et al. Multiplex quantitative analysis of tumor-infiltrating lymphocytes and immunotherapy outcome in metastatic melanoma. Clin Cancer Res. 2019;25:2442–9. https://doi.org/10.1158/1078-0432.CCR-18-2652.
Tumeh PC, Harview CL, Yearley JH, et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature. 2014;515:568–71. https://doi.org/10.1038/nature13954.
Schalper KA, Kaftan E, Herbst RS. Predictive biomarkers for PD-1 axis therapies: the hidden treasure or a call for research. Clin Cancer Res. 2016;22:2102–4. https://doi.org/10.1158/1078-0432.CCR-16-0169.
Shaikh WR, Dusza SW, Weinstock MA, Oliveria SA, Geller AC, Halpern AC. Melanoma thickness and survival trends in the United States, 1989 to 2009. J Natl Cancer Inst. 2016;108:1190. Doi:https://doi.org/10.1093/jnci/djv294.
Shen W, Sakamoto N, Yang L. Melanoma-specific mortality and competing mortality in patients with non-metastatic malignant melanoma: a population-based analysis. BMC Cancer. 2016;16:413. https://doi.org/10.1186/s12885-016-2438-3.
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Straker, R.J., Krupp, K., Sharon, C.E. et al. Prognostic Significance of Primary Tumor-Infiltrating Lymphocytes in a Contemporary Melanoma Cohort. Ann Surg Oncol 29, 5207–5216 (2022). https://doi.org/10.1245/s10434-022-11478-4