Tumor-infiltrating lymphocytes

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Micrograph showing tumor infiltrating lymphocytes in a case of colorectal cancer. H&E stain.

Tumor-infiltrating lymphocytes, also tumour infiltrating lymphocytes, are white blood cells that have left the bloodstream and migrated into a tumor. They include T cells and B cells and are part of the larger category of ‘tumor-infiltrating immune cells’ which consist of both mononuclear and polymorphonuclear immune cells, (i.e., T cells, B cells, natural killer cells, macrophages, neutrophils, dendritic cells, mast cells, eosinophils, basophils, etc.) in variable proportions.  Their abundance varies about tumor type and stage and in some cases relate to disease prognosis [1][2][3][4][5]

Tumor-infiltrating immune cells can often be found in the stroma and within the tumour itself.

Their functions can dynamically change throughout tumor progression and in response to anticancer therapy[2][3][4][5]

TILs are implicated in killing tumor cells. The presence of lymphocytes in tumors is often associated with better clinical outcomes (after surgery or immunotherapy).[6][7][8][9]

Detection and characteristics[edit]

When TILs are present, the lymphocytes are found between the tumor cells; cells in the stroma surrounding the tumor cells do not count.[10] It should be noted that histologic definitions for TILs vary.

CD3 has been used to detect lymphocytes in tumor samples.[8] Tumor immune infiltration can also be determined using gene expression methods like Micro array or RNA Sequencing. Detection of gene expression specific for different kind of immune cell populations can then be used to determine the degree of lymphocyte infiltration as has been shown in breast cancer.[11] An active immune environment within the tumor often indicates a better prognosis as can be determined by the Immunological constant of rejection.[12]

Associations with cancer prognosis[edit]

Colorectal cancer[edit]

In colorectal cancer, tumor-infiltrating lymphocytes are associated with microsatellite instability cancers, as may be seen in Lynch syndrome.[13]

TILs are needed for checkpoint inhibitor therapy to work in GI cancers.[8][9]

Melanoma[edit]

They are an important prognostic factor in melanoma and higher levels being associated with a better outcome.[14][15][9]

Ovarian cancer[edit]

TILs are also associated with better outcomes in epithelial ovarian cancer.[7][9]

Use in an autologous cell therapy[edit]

They are key to an experimental autologous cell therapy (Contego) for metastatic melanoma.[16]

Use as an adoptive cell transfer therapy[edit]

History[edit]

The use of TILs as an adoptive cell transfer therapy to treat cancer was pioneered by Dr. Steven Rosenberg at the National Cancer Institute.[citation needed] Autologous lymphocytes are isolated from patients’ tumors and cultured to large numbers of cells in vitro. Prior to TIL treatment, patients are given nonmyeloablative chemotherapy to deplete native lymphocytes that can inhibit the response. Once lymphodepletion is completed, patients are infused with TILs in combination with interleukin 2 (IL-2). Lion Biotechnologies is developing adoptive cell transfer with TILs as a cancer therapy.

For melanoma[edit]

Several centres are currently working on TIL melanoma treatment protocol, including the Ella Institute in Sheba Hospital, Israel[17] and Copenhagen University Hospital at Herlev, Denmark [18][19]

Clinical trials have used TILs to treat patients with metastatic melanoma. Tumor reduction of 50% or more was observed in about half of patients.[20][21][22][23] Some patients experienced complete responses with no detectable tumor remaining years after treatment.[24]

For other cancers[edit]

Clinical trials using TILs to treat digestive tract cancers, such as colorectal cancer,[25] and cancers associated with the human papilloma virus (HPV), such as cervical cancer,[26] are ongoing.

Under investigation are the use of TILs to treat other tumors, including lung, ovarian, bladder, and breast.

See also[edit]

References[edit]

  1. ^ "Breast Cancer Immunology". Oncology Times. 38: 18–19. doi:10.1097/01.COT.0000483221.52404.e3. 
  2. ^ a b Hanahan D, Coussens LM (March 2012). "Accessories to the crime: functions of cells recruited to the tumor microenvironment". Cancer Cell. 21 (3): 309–22. doi:10.1016/j.ccr.2012.02.022. PMID 22439926. 
  3. ^ a b Coussens LM, Zitvogel L, Palucka AK (January 2013). "Neutralizing tumor-promoting chronic inflammation: a magic bullet?". Science. 339 (6117): 286–91. doi:10.1126/science.1232227. PMC 3591506Freely accessible. PMID 23329041. 
  4. ^ a b Engblom C, Pfirschke C, Zilionis R, Da Silva Martins J, Bos SA, Courties G, Rickelt S, Severe N, Baryawno N, Faget J, Savova V, Zemmour D, Kline J, Siwicki M, Garris C, Pucci F, Liao HW, Lin YJ, Newton A, Yaghi OK, Iwamoto Y, Tricot B, Wojtkiewicz GR, Nahrendorf M, Cortez-Retamozo V, Meylan E, Hynes RO, Demay M, Klein A, Bredella MA, Scadden DT, Weissleder R, Pittet MJ (December 2017). "Osteoblasts remotely supply lung tumors with cancer-promoting SiglecFhigh neutrophils". Science. 358 (6367): eaal5081. doi:10.1126/science.aal5081. PMID 29191879. 
  5. ^ a b Gentles AJ, Newman AM, Liu CL, Bratman SV, Feng W, Kim D, Nair VS, Xu Y, Khuong A, Hoang CD, Diehn M, West RB, Plevritis SK, Alizadeh AA (August 2015). "The prognostic landscape of genes and infiltrating immune cells across human cancers". Nature Medicine. 21 (8): 938–945. doi:10.1038/nm.3909. PMC 4852857Freely accessible. PMID 26193342. 
  6. ^ Vánky F, Klein E, Willems J, Böök K, Ivert T, Péterffy A, Nilsonne U, Kreicbergs A, Aparisi T (1986). "Lysis of autologous tumor cells by blood lymphocytes tested at the time of surgery. Correlation with the postsurgical clinical course". Cancer Immunology, Immunotherapy. 21 (1): 69–76. doi:10.1007/BF00199380. PMID 3455878. 
  7. ^ a b Zhang L, Conejo-Garcia JR, Katsaros D, Gimotty PA, Massobrio M, Regnani G, Makrigiannakis A, Gray H, Schlienger K, Liebman MN, Rubin SC, Coukos G (January 2003). "Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer". The New England Journal of Medicine. 348 (3): 203–13. doi:10.1056/NEJMoa020177. PMID 12529460. 
  8. ^ a b c Immunotherapy Doubts Fading in GI Cancers. April 2016
  9. ^ a b c d Syn, Nicholas L; Teng, Michele W L; Mok, Tony S K; Soo, Ross A. "De-novo and acquired resistance to immune checkpoint targeting". The Lancet Oncology. 18 (12): e731–e741. doi:10.1016/s1470-2045(17)30607-1. 
  10. ^ Garg K, Soslow RA (August 2009). "Lynch syndrome (hereditary non-polyposis colorectal cancer) and endometrial carcinoma". Journal of Clinical Pathology. 62 (8): 679–84. doi:10.1136/jcp.2009.064949. PMID 19638537. 
  11. ^ Bedognetti D, Hendrickx W, Marincola FM, Miller LD (November 2015). "Prognostic and predictive immune gene signatures in breast cancer". Current Opinion in Oncology. 27 (6): 433–44. doi:10.1097/cco.0000000000000234. PMID 26418235. 
  12. ^ Bedognetti D, Hendrickx W, Ceccarelli M, Miller LD, Seliger B (April 2016). "Disentangling the relationship between tumor genetic programs and immune responsiveness". Current Opinion in Immunology. 39: 150–8. doi:10.1016/j.coi.2016.02.001. PMID 26967649. 
  13. ^ Iacopetta B, Grieu F, Amanuel B (December 2010). "Microsatellite instability in colorectal cancer". Asia-Pacific Journal of Clinical Oncology. 6 (4): 260–9. doi:10.1111/j.1743-7563.2010.01335.x. PMID 21114775. 
  14. ^ Spatz; et al. (2007). "Protective effect of a brisk tumor infiltrating lymphocyte infiltrate in melanoma: An EORTC melanoma group study". Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S (June 20 Supplement), 2007: 8519. 
  15. ^ Galon; et al. (2006). "Type, Density, and Location of Immune Cells Within Human Colorectal Tumors Predict Clinical Outcome". Science 29 September 2006: 313 (5795), 1960-1964. 
  16. ^ "Genesis Biopharma expands clinical focus to develop Contego for Stage IV metastatic melanoma". June 2011. 
  17. ^ "Clinical Responses in a Phase II Study Using Adoptive Transfer of Short-term Cultured Tumor Infiltration Lymphocytes in Metastatic Melanoma Patients" (PDF). 
  18. ^ "Adoptive cell therapy with autologous tumor infiltrating lymphocytes and low-dose Interleukin-2 in metastatic melanoma patients". 
  19. ^ Donia M, Hansen M, Sendrup SL, Iversen TZ, Ellebæk E, Andersen MH, Straten PT, Svane IM (February 2013). "Methods to improve adoptive T-cell therapy for melanoma: IFN-γ enhances anticancer responses of cell products for infusion". The Journal of Investigative Dermatology. 133 (2): 545–52. doi:10.1038/jid.2012.336. PMID 23014345. 
  20. ^ Dudley ME, Yang JC, Sherry R, Hughes MS, Royal R, Kammula U, Robbins PF, Huang J, Citrin DE, Leitman SF, Wunderlich J, Restifo NP, Thomasian A, Downey SG, Smith FO, Klapper J, Morton K, Laurencot C, White DE, Rosenberg SA (November 2008). "Adoptive cell therapy for patients with metastatic melanoma: evaluation of intensive myeloablative chemoradiation preparative regimens". Journal of Clinical Oncology. 26 (32): 5233–9. doi:10.1200/JCO.2008.16.5449. PMC 2652090Freely accessible. PMID 18809613. 
  21. ^ Radvanyi LG, Bernatchez C, Zhang M, Fox PS, Miller P, Chacon J, Wu R, Lizee G, Mahoney S, Alvarado G, Glass M, Johnson VE, McMannis JD, Shpall E, Prieto V, Papadopoulos N, Kim K, Homsi J, Bedikian A, Hwu WJ, Patel S, Ross MI, Lee JE, Gershenwald JE, Lucci A, Royal R, Cormier JN, Davies MA, Mansaray R, Fulbright OJ, Toth C, Ramachandran R, Wardell S, Gonzalez A, Hwu P (December 2012). "Specific lymphocyte subsets predict response to adoptive cell therapy using expanded autologous tumor-infiltrating lymphocytes in metastatic melanoma patients". Clinical Cancer Research. 18 (24): 6758–70. doi:10.1158/1078-0432.CCR-12-1177. PMC 3525747Freely accessible. PMID 23032743. 
  22. ^ Pilon-Thomas S, Kuhn L, Ellwanger S, Janssen W, Royster E, Marzban S, Kudchadkar R, Zager J, Gibney G, Sondak VK, Weber J, Mulé JJ, Sarnaik AA (October 2012). "Efficacy of adoptive cell transfer of tumor-infiltrating lymphocytes after lymphopenia induction for metastatic melanoma". Journal of Immunotherapy. 35 (8): 615–20. doi:10.1097/CJI.0b013e31826e8f5f. PMID 22996367. 
  23. ^ Besser MJ, Shapira-Frommer R, Treves AJ, Zippel D, Itzhaki O, Hershkovitz L, Levy D, Kubi A, Hovav E, Chermoshniuk N, Shalmon B, Hardan I, Catane R, Markel G, Apter S, Ben-Nun A, Kuchuk I, Shimoni A, Nagler A, Schachter J (May 2010). "Clinical responses in a phase II study using adoptive transfer of short-term cultured tumor infiltration lymphocytes in metastatic melanoma patients". Clinical Cancer Research. 16 (9): 2646–55. doi:10.1158/1078-0432.CCR-10-0041. PMID 20406835. 
  24. ^ Rosenberg SA, Yang JC, Sherry RM, Kammula US, Hughes MS, Phan GQ, Citrin DE, Restifo NP, Robbins PF, Wunderlich JR, Morton KE, Laurencot CM, Steinberg SM, White DE, Dudley ME (July 2011). "Durable complete responses in heavily pretreated patients with metastatic melanoma using T-cell transfer immunotherapy". Clinical Cancer Research. 17 (13): 4550–7. doi:10.1158/1078-0432.CCR-11-0116. PMC 3131487Freely accessible. PMID 21498393. 
  25. ^ Clinical trial number NCT01174121 for "A Phase II Study Using Short-Term Cultured, CD8+-Enriched Autologous Tumor-infiltrating Lymphocytes Following a Lymphocyte Depleting Regimen in Metastatic Digestive Tract Cancers" at ClinicalTrials.gov
  26. ^ Clinical trial number NCT01585428 for "A Phase II Study of Lymphodepletion Followed by Autologous Tumor-Infiltrating Lymphocytes and High-Dose Adesleukin for Human Papillomavirus-Associated Cancers" at ClinicalTrials.gov

External links[edit]