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Assessing Tumor-infiltrating Lymphocytes in Solid Tumors: A Practical Review for Pathologists and Proposal for a Standardized Method From the International Immunooncology Biomarkers Working Group Part 1 Assessing the Host Immune Response, TILs in Invasive Breast Carcinoma and Ductal Carcinoma In Situ, Metastatic Tumor Deposits and Areas for Further Research

Hendry, Shona MBBS*,†; Salgado, Roberto MD‡,§; Gevaert, Thomas MD∥,¶; Russell, Prudence A. MBBS#,**; John, Tom PhD††,‡‡,§§; Thapa, Bibhusal MBBS, MS‡‡,∥∥; Christie, Michael MBBS, PhD¶¶; van de Vijver, Koen MD, PhD##; Estrada, M.V. MD***; Gonzalez-Ericsson, Paula I. MD†††; Sanders, Melinda MD‡‡‡; Solomon, Benjamin MBBS, PhD§§§; Solinas, Cinzia MD∥∥∥; Van den Eynden, Gert G.G.M. MD, PhD∥∥∥,¶¶¶; Allory, Yves MD, PhD###,****,††††; Preusser, Matthias MD‡‡‡‡; Hainfellner, Johannes MD§§§§; Pruneri, Giancarlo MD∥∥∥∥,¶¶¶¶; Vingiani, Andrea MD∥∥∥∥,¶¶¶¶; Demaria, Sandra MD####; Symmans, Fraser MBChB*****; Nuciforo, Paolo MD†††††; Comerma, Laura MD, PhD†††††; Thompson, E.A. PhD‡‡‡‡‡; Lakhani, Sunil BSc, MBBS, PhD§§§§§,∥∥∥∥∥; Kim, Seong-Rim MD¶¶¶¶¶; Schnitt, Stuart MD#####,******; Colpaert, Cecile MD, PhD††††††; Sotiriou, Christos MD, PhD‡‡‡‡‡‡; Scherer, Stefan J. MD, PhD§§§§§§; Ignatiadis, Michail MD, PhD‡‡‡‡‡‡; Badve, Sunil MBBS∥∥∥∥∥∥; Pierce, Robert H. MD¶¶¶¶¶¶; Viale, Giuseppe MD######; Sirtaine, Nicolas MD*******; Penault-Llorca, Frederique MD, PhD†††††††,‡‡‡‡‡‡‡; Sugie, Tomohagu MD§§§§§§§; Fineberg, Susan MD∥∥∥∥∥∥∥,¶¶¶¶¶¶¶; Paik, Soonmyung MD¶¶¶¶¶,#######; Srinivasan, Ashok MD¶¶¶¶¶; Richardson, Andrea MD, PhD******,********,††††††††; Wang, Yihong MD, PhD‡‡‡‡‡‡‡‡,§§§§§§§§; Chmielik, Ewa MD∥∥∥∥∥∥∥∥,¶¶¶¶¶¶¶¶; Brock, Jane MBBS, PhD******,********; Johnson, Douglas B. MD#########,*********; Balko, Justin PharmD, PhD#########,*********; Wienert, Stephan DMedSci†††††††††,‡‡‡‡‡‡‡‡‡; Bossuyt, Veerle MD§§§§§§§§§; Michiels, Stefan PhD∥∥∥∥∥∥∥∥∥; Ternes, Nils PhD∥∥∥∥∥∥∥∥∥; Burchardi, Nicole PhD¶¶¶¶¶¶¶¶¶; Luen, Stephen J. MBChB†,§§§; Savas, Peter MBBS†,§§§; Klauschen, Frederick MD, PhD, MSc†††††††††; Watson, Peter H. MBBChir#########,**********; Nelson, Brad H. PhD**********,††††††††††,‡‡‡‡‡‡‡‡‡‡; Criscitiello, Carmen MD, PhD∥∥∥∥; O’Toole, Sandra MD, PhD§§§§§§§§§§,¶¶¶¶¶¶¶¶¶¶; Larsimont, Denis MD*******; de Wind, Roland MD*******; Curigliano, Giuseppe MD, PhD∥∥∥∥; André, Fabrice MD, PhD¶¶¶¶¶¶¶¶¶,##########; Lacroix-Triki, Magali MD¶¶¶¶¶¶¶¶¶¶; van de Vijver, Mark MD, PhD***********; Rojo, Federico MD†††††††††††; Floris, Giuseppe MD, PhD‡‡‡‡‡‡‡‡‡‡‡; Bedri, Shahinaz MBBS§§§§§§§§§§§; Sparano, Joseph MD∥∥∥∥∥∥∥∥∥∥∥; Rimm, David MD, PhD§§§§§§§§§; Nielsen, Torsten MD, PhD¶¶¶¶¶¶¶¶¶¶¶; Kos, Zuzana MD###########; Hewitt, Stephen MD, PhD************; Singh, Baljit MD††††††††††††; Farshid, Gelareh MBBS, MD, MPH‡‡‡‡‡‡‡‡‡‡‡‡,§§§§§§§§§§§§; Loibl, Sibylle MD, PhD¶¶¶¶¶¶¶¶¶; Allison, Kimberly H. MD∥∥∥∥∥∥∥∥∥∥∥∥; Tung, Nadine MD¶¶¶¶¶¶¶¶¶¶¶¶; Adams, Sylvia MD############,*************; Willard-Gallo, Karen PhD∥∥∥; Horlings, Hugo M. MD, PhD†††††††††††††; Gandhi, Leena MD, PhD*************,‡‡‡‡‡‡‡‡‡‡‡‡‡; Moreira, Andre MD, PhD§§§§§§§§§§§§§; Hirsch, Fred MD, PhD∥∥∥∥∥∥∥∥∥∥∥∥∥; Dieci, Maria V. MD¶¶¶¶¶¶¶¶¶¶¶¶¶,#############; Urbanowicz, Maria MD**************; Brcic, Iva MD, PhD††††††††††††††; Korski, Konstanty MD, PhD‡‡‡‡‡‡‡‡‡‡‡‡‡‡; Gaire, Fabien PhD‡‡‡‡‡‡‡‡‡‡‡‡‡‡; Koeppen, Hartmut MD, PhD§§§§§§§§§§§§§§; Lo, Amy MD, MS§§§§§§§§§§§§§§,∥∥∥∥∥∥∥∥∥∥∥∥∥∥; Giltnane, Jennifer MD, PhD§§§§§§§§§§§§§§; Rebelatto, Marlon C. PhD¶¶¶¶¶¶¶¶¶¶¶¶¶¶; Steele, Keith E. PhD¶¶¶¶¶¶¶¶¶¶¶¶¶¶; Zha, Jiping MD, PhD¶¶¶¶¶¶¶¶¶¶¶¶¶¶; Emancipator, Kenneth MD##############; Juco, Jonathan W. MD##############; Denkert, Carsten MD, PhD†††††††††; Reis-Filho, Jorge MD, PhD***************; Loi, Sherene MD, PhD§§§; Fox, Stephen B. BSc, MBChB, DPhil*,†

doi: 10.1097/PAP.0000000000000162
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Assessment of tumor-infiltrating lymphocytes (TILs) in histopathologic specimens can provide important prognostic information in diverse solid tumor types, and may also be of value in predicting response to treatments. However, implementation as a routine clinical biomarker has not yet been achieved. As successful use of immune checkpoint inhibitors and other forms of immunotherapy become a clinical reality, the need for widely applicable, accessible, and reliable immunooncology biomarkers is clear. In part 1 of this review we briefly discuss the host immune response to tumors and different approaches to TIL assessment. We propose a standardized methodology to assess TILs in solid tumors on hematoxylin and eosin sections, in both primary and metastatic settings, based on the International Immuno-Oncology Biomarker Working Group guidelines for TIL assessment in invasive breast carcinoma. A review of the literature regarding the value of TIL assessment in different solid tumor types follows in part 2. The method we propose is reproducible, affordable, easily applied, and has demonstrated prognostic and predictive significance in invasive breast carcinoma. This standardized methodology may be used as a reference against which other methods are compared, and should be evaluated for clinical validity and utility. Standardization of TIL assessment will help to improve consistency and reproducibility in this field, enrich both the quality and quantity of comparable evidence, and help to thoroughly evaluate the utility of TILs assessment in this era of immunotherapy.

Supplemental Digital Content is available in the text.

Departments of *Pathology

§§§Medical Oncology, Peter MacCallum Cancer Centre, Melbourne

The Sir Peter MacCallum Department of Oncology

Departments of **Pathology

∥∥Medicine, University of Melbourne

¶¶Department of Anatomical Pathology, Royal Melbourne Hospital, Parkville

#Department of Anatomical Pathology, St Vincent’s Hospital Melbourne, Fitzroy

††Department of Medical Oncology, Austin Health

‡‡Olivia Newton-John Cancer Research Institute, Heidelberg

§§School of Cancer Medicine, La Trobe University, Bundoora

§§§§§Centre for Clinical Research and School of Medicine, The University of Queensland

∥∥∥∥∥Pathology Queensland, Royal Brisbane and Women’s Hospital, Brisbane

§§§§§§§§§§The Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst

∥∥∥∥∥∥∥∥∥∥Australian Clinical Labs, Bella Vista

‡‡‡‡‡‡‡‡‡‡‡‡Directorate of Surgical Pathology, SA Pathology

§§§§§§§§§§§§Discipline of Medicine, Adelaide University, Adelaide, Australia

***********Department of Surgical Oncology, Netherlands Cancer Institute

†††††††††††††Department of Pathology

##Divisions of Diagnostic Oncology & Molecular Pathology, Netherlands Cancer Institute-Antoni van Leeuwenhoek, Amsterdam, The Netherlands

###Université Paris-Est

****INSERM, UMR 955

††††Département de pathologie, APHP, Hôpital Henri-Mondor, Créteil

∥∥∥∥∥∥∥∥∥Service de Biostatistique et d’Epidémiologie, Gustave Roussy, CESP, Inserm U1018, Université-Paris Sud, Université Paris-Saclay

¶¶¶¶¶¶¶¶¶¶INSERM Unit U981, and Department of Medical Oncology, Gustave Roussy, Villejuif

##########Faculté de Médecine, Université Paris Sud, Kremlin-Bicêtre

†††††††Department of Surgical Pathology and Biopathology, Jean Perrin Comprehensive Cancer Centre

‡‡‡‡‡‡‡University of Auvergne UMR1240, Clermont-Ferrand, France

‡‡‡‡Department of Medicine, Clinical Division of Oncology

§§§§Institute of Neurology, Comprehensive Cancer Centre Vienna, Medical University of Vienna, Vienna

††††††††††††††Institute of Pathology, Medical University of Graz, Austria

∥∥∥∥European Institute of Oncology

¶¶¶¶School of Medicine

######Department of Pathology, Istituto Europeo di Oncologia, University of Milan, Milan

¶¶¶¶¶¶¶¶¶¶¶¶¶Department of Surgery, Oncology and Gastroenterology, University of Padova

#############Medical Oncology 2, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy

†††††Molecular Oncology Group, Vall d’Hebron Institute of Oncology, Barcelona

†††††††††††Pathology Department, IIS-Fundacion Jimenez Diaz, UAM, Madrid, Spain

§Department of Pathology and TCRU, GZA

¶¶¶Department of Pathology, GZA Ziekenhuizen, Antwerp

Laboratory of Experimental Urology, Department of Development and Regeneration, KU Leuven

‡‡‡‡‡‡‡‡‡‡‡Department of Pathology, University Hospital Leuven, Leuven, Belgium

Department of Pathology, AZ Klina, Brasschaat

††††††Department of Pathology, GZA Ziekenhuizen, Sint-Augustinus, Wilrijk

∥∥∥Molecular Immunology Unit

‡‡‡‡‡‡Department of Medical Oncology, Institut Jules Bordet, Université Libre de Bruxelles

Breast Cancer Translational Research Laboratory/Breast International Group, Institut Jules Bordet

**************European Organisation for Research and Treatment of Cancer (EORTC) Headquarters

*******Department of Pathology, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium

§§§§§§§Department of Surgery, Kansai Medical School, Hirakata, Japan

#######Severance Biomedical Science Institute and Department of Medical Oncology, Yonsei University College of Medicine, Seoul, South Korea

∥∥∥∥∥∥∥∥Tumor Pathology Department, Maria Sklodowska-Curie Memorial Cancer Center

¶¶¶¶¶¶¶¶Institute of Oncology, Gliwice Branch, Gliwice, Poland

‡‡‡‡‡‡‡‡‡‡‡‡‡‡Pathology and Tissue Analytics, Roche Innovation Centre Munich, Penzberg

†††††††††Institute of Pathology, Charité Universitätsmedizin Berlin

‡‡‡‡‡‡‡‡‡VMscope GmbH, Berlin

¶¶¶¶¶¶¶¶¶German Breast Group GmbH, Neu-Isenburg, Germany

**********Trev & Joyce Deeley Research Centre, British Columbia Cancer Agency

††††††††††Department of Biochemistry and Microbiology, University of Victoria, Victoria

Departments of ‡‡‡‡‡‡‡‡‡‡Medical Genetics

#########Pathology and Laboratory Medicine

¶¶¶¶¶¶¶¶¶¶¶Department of Pathology and Laboratory Medicine, Genetic Pathology Evaluation Centre, University of British Columbia, Vancouver, BC

###########Department of Pathology and Laboratory Medicine, University of Ottawa, Ottawa, Canada

§§§§§§§§§§§Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, Doha, Qatar

‡‡‡‡‡‡‡‡Department of Pathology and Laboratory Medicine, Rhode Island Hospital and Lifespan Medical Center

§§§§§§§§Warren Alpert Medical School of Brown University, Providence

¶¶¶¶¶National Surgical Adjuvant Breast and Bowel Project Operations Center/NRG Oncology, Pittsburgh, PA

†††Breast Cancer Research Program, Vanderbilt Ingram Cancer Center, Vanderbilt University

Departments of ‡‡‡Pathology, Microbiology and Immunology

########Department of Medicine, Vanderbilt University Medical Centre

*********Vanderbilt Ingram Cancer Center, Nashville

§§§§§§§§§Department of Pathology, Yale University School of Medicine, New Haven

∥∥∥∥∥∥∥∥∥∥∥Department of Oncology, Montefiore Medical Centre, Albert Einstein College of Medicine

∥∥∥∥∥∥∥Montefiore Medical Center

¶¶¶¶¶¶¶The Albert Einstein College of Medicine, Bronx, NY

********Department of Pathology, Brigham and Women’s Hospital

#####Cancer Research Institute and Department of Pathology, Beth Israel Deaconess Cancer Center

******Harvard Medical School

¶¶¶¶¶¶¶¶¶¶¶¶Division of Hematology-Oncology, Beth Israel Deaconess Medical Center

††††††††Department of Cancer Biology

‡‡‡‡‡‡‡‡‡‡‡‡‡Dana-Farber Cancer Institute, Boston, MA

∥∥∥∥∥∥∥∥∥∥∥∥∥Department of Medicine, Division of Medical Oncology, University of Colorado Anschutz Medical Campus, Aurora, CO

‡‡‡‡‡Department of Cancer Biology, Mayo Clinic, Jacksonville, FL

∥∥∥∥∥∥Department of Pathology and Laboratory Medicine, Indiana University, Indianapolis, IN

¶¶¶¶¶¶Cancer Immunotherapy Trials Network, Central Laboratory and Program in Immunology, Fred Hutchinson Cancer Research Center, Seattle, WA

††††††††††††Department of Pathology, New York University Langone Medical Centre

############New York University Medical School

*************Perlmutter Cancer Center

§§§§§§§§§§§§§Pulmonary Pathology, New York University Center for Biospecimen Research and Development, New York University

***************Department of Pathology, Memorial Sloan-Kettering Cancer Center

####Departments of Radiation Oncology and Pathology, Weill Cornell Medicine, New York, NY

*****Department of Pathology, University of Texas M.D. Anderson Cancer Center, Houston, TX

∥∥∥∥∥∥∥∥∥∥∥∥Pathology Department, Stanford University Medical Centre, Stanford

∥∥∥∥∥∥∥∥∥∥∥∥∥∥Department of Pathology, Stanford University, Palo Alto

***Department of Pathology, School of Medicine, University of California, San Diego

§§§§§§§§§§§§§§Research Pathology, Genentech Inc., South San Francisco, CA

*************Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda

¶¶¶¶¶¶¶¶¶¶¶¶¶¶Translational Sciences, MedImmune, Gaithersberg, MD

§§§§§§Academic Medical Innovation, Novartis Pharmaceuticals Corporation, East Hanover

##############Translational Medicine, Merck & Co. Inc., Kenilworth, NJ

Supported by a grant from the Breast Cancer Research Foundation (BRCF) (R.S.); ISCiii/FEDER (CIBERONCO, PI15/00934) (F.R.); the NIH (NCI K23 CA204726) (D.B.J.).

The authors have no conflicts of interest to disclose.

Reprints: Roberto Salgado, MD, Department of Pathology, Oosterveldlaan 24, 2610 Wilrijk, Belgium (e-mail: roberto@salgado.be).

All figures can be viewed online in color at www.anatomicpathology.com.

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