Tumor-infiltrating lymphocytes

TILs can be found between the tumor cells, as TILs in the stroma surrounding the tumor cells do not count. {{clarify|date=May 2025}} {{cite journal | vauthors = Garg K, Soslow RA | title = Lynch syndrome (hereditary non-polyposis colorectal cancer) and endometrial carcinoma | journal = Journal of Clinical Pathology | volume = 62 | issue = 8 | pages = 679–84 | date = August 2009 | pmid = 19638537 | doi = 10.1136/jcp.2009.064949 | doi-access = free }} TILs are often found floating around the tumor without actual penetration or action on the tumor cells. {{source?|date=May 2025}} Histologic definitions for TILs vary.

CD3 has been used to detect lymphocytes in tumor samples.{{Cite web |url=http://global.onclive.com/conference-coverage/SOGO-2016/immunotherapy-doubts-fading-in-gi-cancers |title=Immunotherapy Doubts Fading in GI Cancers. April 2016 |access-date=2016-04-30 |archive-date=2016-04-30 |archive-url=https://web.archive.org/web/20160430065308/http://global.onclive.com/conference-coverage/SOGO-2016/immunotherapy-doubts-fading-in-gi-cancers |url-status=dead }} Tumor immune infiltration can also be determined using gene expression methods like Microarray or RNA Sequencing through deconvolution methods such as CIBERSORT.{{Cite journal|last1=Nirmal|first1=Ajit J.|last2=Regan|first2=Tim|last3=Shih|first3=Barbara B.|last4=Hume|first4=David A.|last5=Sims|first5=Andrew H.|last6=Freeman|first6=Tom C.|date=2018-11-01|title=Immune Cell Gene Signatures for Profiling the Microenvironment of Solid Tumors|journal=Cancer Immunology Research|language=en|volume=6|issue=11|pages=1388–1400|doi=10.1158/2326-6066.CIR-18-0342|issn=2326-6066|pmid=30266715|doi-access=free|hdl=20.500.11820/e72749a6-a382-44ef-8f93-d58b3353e97c|hdl-access=free}}{{Cite journal|last1=Newman|first1=Aaron M|last2=Liu|first2=Chih Long|last3=Green|first3=Michael R|last4=Gentles|first4=Andrew J|last5=Feng|first5=Weiguo|last6=Xu|first6=Yue|last7=Hoang|first7=Chuong D|last8=Diehn|first8=Maximilian|last9=Alizadeh|first9=Ash A|date=2015-03-30|title=Robust enumeration of cell subsets from tissue expression profiles|journal=Nature Methods|language=En|volume=12|issue=5|pages=453–457|doi=10.1038/nmeth.3337|issn=1548-7091|pmc=4739640|pmid=25822800}} Such methods allow for systematic TIL enumeration and characterization of the tumor microenvironment in diverse cancer types and across thousands of tumors, an approach largely led by Ash Alizadeh, Ajit Johnson among others. 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.{{cite journal | vauthors = Bedognetti D, Hendrickx W, Marincola FM, Miller LD | title = Prognostic and predictive immune gene signatures in breast cancer | journal = Current Opinion in Oncology | volume = 27 | issue = 6 | pages = 433–44 | date = November 2015 | pmid = 26418235 | doi = 10.1097/cco.0000000000000234 | s2cid = 30713069 | doi-access = free }} An active immune environment within the tumor often indicates a better prognosis as can be determined by the Immunological constant of rejection.{{cite journal | vauthors = Bedognetti D, Hendrickx W, Ceccarelli M, Miller LD, Seliger B | title = Disentangling the relationship between tumor genetic programs and immune responsiveness | journal = Current Opinion in Immunology | volume = 39 | pages = 150–8 | date = April 2016 | pmid = 26967649 | doi = 10.1016/j.coi.2016.02.001 }}

They are key to an experimental autologous cell therapy (Contego) for metastatic melanoma.{{cite news |url=http://www.news-medical.net/news/20110606/Genesis-Biopharma-expands-clinical-focus-to-develop-Contego-for-Stage-IV-metastatic-melanoma.aspx |date=June 2011 |title=Genesis Biopharma expands clinical focus to develop Contego for Stage IV metastatic melanoma }} Autologous TIL therapy for metastatic melanoma has broad T cell recognition of both defined and undefined tumor antigens against all human leukocyte antigen (HLA) restrictions. TILs can not only recognize over-expressed self/melanocyte differentiation antigens, such as Melan-A/MART-1 (melanoma-specific), gp100, tyrosinase, and survivin, but TILs can also recognize other unknown antigens specific to the tumor and individual patient.{{cite journal | vauthors = Restifo NP, Dudley ME, Rosenberg SA | title = Adoptive immunotherapy for cancer: harnessing the T cell response | journal = Nature Reviews. Immunology | volume = 12 | issue = 4 | pages = 269–81 | date = March 2012 | pmid = 22437939 | pmc = 6292222 | doi = 10.1038/nri3191 }}

The use of TILs as an adoptive cell transfer therapy to treat cancer was pioneered by Dr. Steven Rosenberg and colleagues at the Surgery Branch of the National Cancer Institute (NCI).{{cite journal | vauthors = Lizée G, Overwijk WW, Radvanyi L, Gao J, Sharma P, Hwu P | title = Harnessing the power of the immune system to target cancer | journal = Annual Review of Medicine | volume = 64 | issue = 1 | pages = 71–90 | date = 2013-01-14 | pmid = 23092383 | doi = 10.1146/annurev-med-112311-083918 }} Rosenberg and colleagues have conducted clinical trials for more than two decades using TIL adoptive cell therapy for melanoma.{{cite journal | vauthors = 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 | title = Durable complete responses in heavily pretreated patients with metastatic melanoma using T-cell transfer immunotherapy | journal = Clinical Cancer Research | volume = 17 | issue = 13 | pages = 4550–7 | date = July 2011 | pmid = 21498393 | pmc = 3131487 | doi = 10.1158/1078-0432.CCR-11-0116 }} TIL adoptive cell therapy is now a routine regimen in centers across the world, including MD Anderson Cancer Center, where the objective response rates originally observed at the NCI have been reproduced.{{cite journal | vauthors = 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 | title = Clinical responses in a phase II study using adoptive transfer of short-term cultured tumor infiltration lymphocytes in metastatic melanoma patients | journal = Clinical Cancer Research | volume = 16 | issue = 9 | pages = 2646–55 | date = May 2010 | pmid = 20406835 | doi = 10.1158/1078-0432.CCR-10-0041 | doi-access = free }}{{cite journal | vauthors = 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 | title = Specific lymphocyte subsets predict response to adoptive cell therapy using expanded autologous tumor-infiltrating lymphocytes in metastatic melanoma patients | journal = Clinical Cancer Research | volume = 18 | issue = 24 | pages = 6758–70 | date = December 2012 | pmid = 23032743 | pmc = 3525747 | doi = 10.1158/1078-0432.CCR-12-1177 }} Several centers currently have established TIL therapy protocols for the treatment of melanoma, including the MD Anderson Cancer Center in Houston, Texas, Ella Institute in Sheba Hospital, Israel, and Copenhagen University Hospital in Herlev, Denmark.{{cite journal | vauthors = Ellebaek E, Iversen TZ, Junker N, Donia M, Engell-Noerregaard L, Met Ö, Hölmich LR, Andersen RS, Hadrup SR, Andersen MH, thor Straten P, Svane IM | title = Adoptive cell therapy with autologous tumor infiltrating lymphocytes and low-dose Interleukin-2 in metastatic melanoma patients | journal = Journal of Translational Medicine | volume = 10 | pages = 169 | date = August 2012 | pmid = 22909342 | pmc = 3514199 | doi = 10.1186/1479-5876-10-169 | doi-access = free }}{{cite journal | vauthors = Donia M, Hansen M, Sendrup SL, Iversen TZ, Ellebæk E, Andersen MH, Straten P, Svane IM | title = Methods to improve adoptive T-cell therapy for melanoma: IFN-γ enhances anticancer responses of cell products for infusion | journal = The Journal of Investigative Dermatology | volume = 133 | issue = 2 | pages = 545–52 | date = February 2013 | pmid = 23014345 | doi = 10.1038/jid.2012.336 | doi-access = free }}

File:Adoptive T-cell therapy.png

In Adoptive T cell transfer therapy, TILs are expanded ex vivo from surgically resected tumors that have been cut into small fragments or from single cell suspensions isolated from the tumor fragments. Multiple individual cultures are established, grown separately and assayed for specific tumor recognition. TILs are expanded over the course of a few weeks with a high dose of IL-2 in 24-well plates. Selected TIL lines that presented best tumor reactivity are then further expanded in a "rapid expansion protocol" (REP), which uses anti-CD3 activation for a typical period of two weeks. The final post-REP TIL is infused back into the patient. The process can also involve a preliminary chemotherapy regimen to deplete endogenous lymphocytes in order to provide the adoptively transferred TILs with enough access to surround the tumor sites. This chemotherapy regimen is given 7 days before the expanded TIL infusion. This involves pretreatment with a combination of fludarabine and cyclophosphamide. Lympho-depletion is thought to eliminate the negative effects of other lymphocytes that may compete for growth factors and decrease anti-tumor effects of the TILs, depleting regulatory or inhibitory lymphocyte populations.{{cite journal | vauthors = Gattinoni L, Finkelstein SE, Klebanoff CA, Antony PA, Palmer DC, Spiess PJ, Hwang LN, Yu Z, Wrzesinski C, Heimann DM, Surh CD, Rosenberg SA, Restifo NP | title = Removal of homeostatic cytokine sinks by lymphodepletion enhances the efficacy of adoptively transferred tumor-specific CD8+ T cells | journal = The Journal of Experimental Medicine | volume = 202 | issue = 7 | pages = 907–12 | date = October 2005 | pmid = 16203864 | pmc = 1397916 | doi = 10.1084/jem.20050732 }}

The combination of TILs with a high dose of IL-2 presents multiple clinical trials demonstrating rates near 50% or more patients effectively responding.{{cite journal | vauthors = Dudley ME, Rosenberg SA | title = Adoptive-cell-transfer therapy for the treatment of patients with cancer | journal = Nature Reviews. Cancer | volume = 3 | issue = 9 | pages = 666–75 | date = September 2003 | pmid = 12951585 | doi = 10.1038/nrc1167 | pmc = 2305722 }} In summary of TIL therapy clinical trials, TIL therapy was found to induce complete and durable regression of metastatic melanoma. Tumor reduction of 50% or more was observed in about half of patients.{{cite journal | vauthors = 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 | title = Adoptive cell therapy for patients with metastatic melanoma: evaluation of intensive myeloablative chemoradiation preparative regimens | journal = Journal of Clinical Oncology | volume = 26 | issue = 32 | pages = 5233–9 | date = November 2008 | pmid = 18809613 | pmc = 2652090 | doi = 10.1200/JCO.2008.16.5449 }}{{cite journal | vauthors = 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 | title = Efficacy of adoptive cell transfer of tumor-infiltrating lymphocytes after lymphopenia induction for metastatic melanoma | journal = Journal of Immunotherapy | volume = 35 | issue = 8 | pages = 615–20 | date = October 2012 | pmid = 22996367 | doi = 10.1097/CJI.0b013e31826e8f5f | pmc = 4467830 }} Some patients experienced complete responses with no detectable tumor remaining years after treatment. In one clinical trials, among the 93 patients treated with TILs, 19 patients had complete remissions that lasted greater than 3 years.

In a randomized, phase III trial conducted between 2014 and 2022 in Denmark and The Netherlands, researchers found that treatment with TILs was superior to ipilimumab in metastatic melanoma. {{cite journal | vauthors = Rohaan M et al. | title = Tumor-Infiltrating Lymphocytes in Advanced Melanoma | journal = New England Journal of Medicine | date = 8 December 2022 | volume = 387 | issue = 23 | pages = 2113–2125 | pmid = 36477031 | doi = 10.1056/NEJMoa2210233 | doi-access = free | hdl = 1887/3566801 | hdl-access = free }}

Clinical trials using TILs to treat digestive tract cancers, such as colorectal cancer,{{ClinicalTrialsGov|NCT01174121|A Phase II Study Using Short-Term Cultured, CD8+-Enriched Autologous Tumor-infiltrating Lymphocytes Following a Lymphocyte Depleting Regimen in Metastatic Digestive Tract Cancers}} and cancers associated with the human papilloma virus (HPV), such as cervical cancer,{{ClinicalTrialsGov|NCT01585428|A Phase II Study of Lymphodepletion Followed by Autologous Tumor-Infiltrating Lymphocytes and High-Dose Adesleukin for Human Papillomavirus-Associated Cancers}} are ongoing. In colorectal cancer, TILs are associated with microsatellite instability cancers, as may be seen in Lynch syndrome.{{cite journal | vauthors = Iacopetta B, Grieu F, Amanuel B | title = Microsatellite instability in colorectal cancer | journal = Asia-Pacific Journal of Clinical Oncology | volume = 6 | issue = 4 | pages = 260–9 | date = December 2010 | pmid = 21114775 | doi = 10.1111/j.1743-7563.2010.01335.x | url = https://zenodo.org/record/895588 | doi-access = free }} Also, TILs are associated with most effective immune checkpoint inhibitor therapy in GI cancers. They are an important prognostic factor in melanoma and higher levels being associated with a better outcome.{{cite web|url=http://www.asco.org/ascov2/Meetings/Abstracts?&vmview=abst_detail_view&confID=47&abstractID=34439|title=Protective effect of a brisk tumor infiltrating lymphocyte infiltrate in melanoma: An EORTC melanoma group study.|author=Spatz|year=2007|publisher=Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S (June 20 Supplement), 2007: 8519|display-authors=etal|access-date=2011-03-02|archive-date=2011-07-25|archive-url=https://web.archive.org/web/20110725021007/http://www.asco.org/ascov2/Meetings/Abstracts?&vmview=abst_detail_view&confID=47&abstractID=34439|url-status=dead}}{{cite journal | vauthors = Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pagès C, Tosolini M, Camus M, Berger A, Wind P, Zinzindohoué F, Bruneval P, Cugnenc PH, Trajanoski Z, Fridman WH, Pagès F | title = Type, density, and location of immune cells within human colorectal tumors predict clinical outcome | journal = Science | volume = 313 | issue = 5795 | pages = 1960–4 | date = September 2006 | pmid = 17008531 | doi = 10.1126/science.1129139 | bibcode = 2006Sci...313.1960G | s2cid = 473931 }} TILs are also associated with better outcomes in epithelial ovarian cancer.

The use of TILs to treat other tumor types, including lung, ovarian, bladder, and breast, are under investigation.

TIL therapy in combination with prior immunotherapy treatment, such as IL-2 and anti-CTLA4 (ipilimumab) had higher response rates and more durable responses in clinical trials. This suggests a synergistic effect of prior immunotherapy with TIL therapy. Current studies involve investigating the roles of chemotherapy drugs in combination with TIL therapy to assess improved response rates and synergistic efficacy.{{cite journal | vauthors = Mbofung RM, McKenzie JA, Malu S, Zhang M, Peng W, Liu C, Kuiatse I, Tieu T, Williams L, Devi S, Ashkin E, Xu C, Huang L, Zhang M, Talukder AH, Tripathi SC, Khong H, Satani N, Muller FL, Roszik J, Heffernan T, Allison JP, Lizee G, Hanash SM, Proia D, Amaria R, Davis RE, Hwu P | title = HSP90 inhibition enhances cancer immunotherapy by upregulating interferon response genes | journal = Nature Communications | volume = 8 | issue = 1 | pages = 451 | date = September 2017 | pmid = 28878208 | pmc = 5587668 | doi = 10.1038/s41467-017-00449-z | bibcode = 2017NatCo...8..451M }}{{cite journal | vauthors = McKenzie JA, Mbofung RM, Malu S, Zhang M, Ashkin E, Devi S, Williams L, Tieu T, Peng W, Pradeep S, Xu C, Zorro Manrique S, Liu C, Huang L, Chen Y, Forget MA, Haymaker C, Bernatchez C, Satani N, Muller F, Roszik J, Kalra A, Heffernan T, Sood A, Hu J, Amaria R, Davis RE, Hwu P | title = The Effect of Topoisomerase I Inhibitors on the Efficacy of T-Cell-Based Cancer Immunotherapy | journal = Journal of the National Cancer Institute | volume = 110 | issue = 7 | pages = 777–786 | date = December 2017 | pmid = 29267866 | pmc = 6037061 | doi = 10.1093/jnci/djx257 }}

• Lymphocyte
• Tumor-Infiltrating Dendritic Cell
• Cancer Immunotherapy
• CAR T-Cell therapy
• T-cells

{{reflist|2}}

• [http://www.cancer.gov/dictionary?CdrID=45329 Tumor infiltrating lymphocyte] entry in the public domain NCI Dictionary of Cancer Terms
• [http://www.lbio.com/ Lion Biotechnologies, Inc.] {{Webarchive|url=https://web.archive.org/web/20160716101439/http://www.lbio.com/ |date=2016-07-16 }}

Category:Lymphocytes

Category:Oncology