Tumor infiltrating lymphocytes (TILs) are commonly detected in breast tumors but their bearing on disease outcome is uncertain. The importance of TILs appears to be subtype-specific and varies depending on the histologic characteristics of the tumor. As our understanding of tumorigenesis is increasing the relevance of immunobiology will become apparent

A Merlo

Adam E Frampton

AM Wolf

BS Nedergaard

C Denkert

C Horlock

DA Oble

EA Rakha

F Pandolfi

GA Calin

J Galon

Jonathan Krell

Justin Stebbing

M Murakami

P Trzonkowski

R Matkowski

RA Figlin

RM Caprioli

SA Rosenberg

SM Mahmoud

English

PubMed

Springer - Publisher Connector

COMMENTARY Open Access
The clinical significance of tumor infiltrating
lymphoctyes in breast cancer: does subtype
matter?
Jonathan Krell*, Adam E Frampton and Justin Stebbing
Abstract
Tumor infiltrating lymphocytes (TILs) are commonly detected in breast tumors but their bearing on disease
outcome is uncertain. The importance of TILs appears to be subtype-specific and varies depending on the
histologic characteristics of the tumor. As our understanding of tumorigenesis is increasing the relevance of
immunobiology will become apparent.
Keywords: Tumor infiltrating lymphocytes, Cancer, Immunobiology
Background
Breast cancer comprises many different subtypes char-
acterized by distinguishing factors such as cell type of
origin, grade and molecular specificities such as Ki-67
levels and receptor status. In recent years further
molecular characteristics such as specific protein and
miRNA expression levels have been associated with
tumor phenotype [1,2], and it appears that multiple
factors determine prognosis in this disease. Although a
greater understanding of cancer cell biology is impera-
tive to improving treatment, it has been shown that
variability in the tumor microenvironment can also
impact on outcome. The past 30 years have accumu-
lated considerable evidence that tumors can elicit a
significant immune response, and the body’s normal
defence mechanisms can play a key role in promoting
or preventing carcinogenesis and tumor spread [3].
Tumors are commonly infiltrated by lymphocytes
(TILs) and their number and subtype are considered to
reflect the host immune response to malignancy [4].
The concept of cancer immunobiology appears to be
an important one and the possible role of TILs in
determining outcome in breast and other cancers
needs further evaluation.
Main text
Cytotoxic CD8+ and CD4+ Th1 T cells function as the
major anti-tumor lymphocytes predominantly through
the production of interferon-gamma (IFN-g), whereas
interleukin-6 (IL-6), tumor-necrosis factor (TNF) and
IL-23 produced by tumor-associated macrophages
(TAM) or myeloid-derived suppressive cells (MDSC) are
believed to promote tumor formation and growth. The
roles played by TILs such as CD4+ CD25+ Foxp3+ TILs
(Tregs) and Th17 cells remains less clear but they
appear to suppress the activity of effector cells including
CD4+ and CD8+ cytotoxic T cells, natural killer cells,
natural killer T cells, and B cells [5,6]. This activity may
promote the survival of cancer cells by affording protec-
tion from both the innate and adaptive immune systems.
Several studies have shown that tumor infiltration by
effector T lymphocytes is associated with favorable
prognosis [7,8], but that higher numbers of Tregs are
associated with progression in a variety of malignancies
[9,10].
The clinical significance of TILs in breast cancer
remains controversial and lymphocyte location and sub-
type appears to determine outcome. High CD4+ and
CD8+ lymphocytic infiltration has been associated with
positive lymph node status as well as worse overall sur-
vival [11], but higher relative levels of CD8+ TILs in ER
negative breast cancer correlates with a better prognosis
[12]. Infiltration by Tregs correlates with tumor inva-
siveness and was shown to represent an independent
* Correspondence: j.krell@imperial.ac.uk
Department of Surgery and Cancer, Imperial College, Hammersmith Hospital,
Du Cane Road, London W12 ONN, UK
Krell et al. BMC Cancer 2012, 12:135
http://www.biomedcentral.com/1471-2407/12/135
© 2012 Krell et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons
Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.
unfavorable prognostic factor, especially in lymph node
positive breast cancer [13]. TIL levels have also been
associated with response to breast cancer therapy. Treg
levels were significantly reduced during treatment with
trastuzumab whilst Th17 frequencies were concomi-
tantly increased [14] and TIL counts have been shown
to represent an independent predictor of response to
neo-adjuvant paclitaxel [15].
The paper by Droeser and coworkers in this addition
of BMC cancer addresses the role of TILs in breast can-
cer and particularly focuses on the differential lympho-
cyte infiltration between histological subtypes.
Furthermore, they utilise an extensive clinical follow-up
database to correlate TIL number in different tumor
compartments with clinico-pathological features and
outcome data. The study is significant in a number of
ways: Firstly, despite being a retrospective study the
sample size is large and certainly sufficient for the pur-
pose of the analysis. Secondly it addresses issues that
have not previously been reported such as T-cell infil-
tration in different histological subtypes and the occur-
rence of IL-17+ lymphocytes in breast cancer tissue.
They used standard immunohistochemical techniques to
stain for TILs in a tissue microarray that included 894
ductal and 164 lobular breast cancers and correlated
lymphocyte counts with clinico-pathological parameters
and survival. The major findings were that ductal and
lobular breast cancers appear to be infiltrated by differ-
ent lymphocyte subpopulations and that in ductal can-
cers increased CD4+ and FOXP3+ lymphocyte
infiltration was linked to more aggressive histological
features (such as higher grade and ER-negative status)
but in lobular carcinomas lymphocyte infiltration was
not linked to any clinico-pathological parameters. Inter-
estingly, although no prognostic relevance could be
attributed to absolute TIL number in either histological
subtype, a FOXP3+ to CD4+ ratio of greater than one
in ductal carcinoma seemed to represent an indepen-
dent favorable prognostic variable. IL-17 lymphocyte
numbers were low in both histological subtypes and no
significant difference between TILs was described
between tumor or stroma tissue.
Discussion
So what is the true clinical relevance of the current
study by Droeser et al.? It provides further evidence that
evaluating Treg tumor infiltration may be a useful
adjunct to current methods used for staging breast can-
cer and may serve as a reliable prognostic biomarker.
However the data suggest that it is the relative infiltra-
tion of different Tregs rather than absolute number that
is most important in this respect. Furthermore, similar
future studies in the metastatic setting may demonstrate
a role for TILs in predicting the behavior of advanced
tumors. The study also suggests a possible role for TILs
as diagnostic biomarkers as there is a clear difference in
lymphoctye infiltration between histological subgroups.
This finding may also provide valuable information as to
how variability in immunogenicity is associated with dif-
ferent tumors or tumor growth patterns. A greater
understanding of the function of TILs within a tumor
might also aid in identifying those patients most likely
to benefit from immunomodulatory therapies in breast
cancer, a strategy that has been used with varying suc-
cess in other tumor types such as melanoma [16] and
renal cell carcinoma [17].
Conclusion
In an era when standard prognostic, predictive and diag-
nostic parameters are ever changing and the use of
extended molecular fingerprint analyses are increasing,
we are continually looking for techniques to further our
understanding of tumor biology and improve patient
outcome. Although further work is clearly required to
fully establish the importance and potential role of TILs
in breast and other malignancies, it seems clear that a
thorough assessment of the immunobiological status of
tumors will go someway to achieving these goals. The
relevance of tumor lymphocyte infiltration cannot be
ignored but needs to be properly evaluated in larger
prospective studies which must encompass the para-
meters set out in this and previous studies.
Authors’ contributions
JK prepared the main text, discussion and conclusion. AEF prepared the
background and edited the manuscript. JS supervised the writing of the
manuscript and edited the draft.
Competing interests
The authors declare that they have no competing interests.
Received: 27 February 2012 Accepted: 3 April 2012
Published: 3 April 2012
References
1. Caprioli RM: Deciphering protein molecular signatures in cancer tissues
to aid in diagnosis, prognosis, and therapy. Cancer Res 2005,
65(23):10642-10645.
2. Calin GA, Croce CM: MicroRNA signatures in human cancers. Nature
reviews Cancer 2006, 6(11):857-866.
3. Pandolfi F, Cianci R, Pagliari D, Casciano F, Bagala C, Astone A, Landolfi R,
Barone C: The Immune Response to Tumors as a Tool toward
Immunotherapy. Clinical & developmental immunology 2011, 2011:894704.
4. Mahmoud SM, Paish EC, Powe DG, Macmillan RD, Grainge MJ, Lee AH,
Ellis IO, Green AR: Tumor-infiltrating CD8+ lymphocytes predict clinical
outcome in breast cancer. J Clin Oncol 2011, 29(15):1949-1955.
5. Trzonkowski P, Szmit E, Mysliwska J, Dobyszuk A, Mysliwski A: CD4 + CD25
+ T regulatory cells inhibit cytotoxic activity of T CD8+ and NK
lymphocytes in the direct cell-to-cell interaction. Clin Immunol 2004,
112(3):258-267.
6. Murakami M, Sakamoto A, Bender J, Kappler J, Marrack P: CD25 + CD4+ T
cells contribute to the control of memory CD8+ T cells. Proc Natl Acad
Sci USA 2002, 99(13):8832-8837.
7. Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pages C,
Tosolini M, Camus M, Berger A, Wind P, et al: Type, density, and location
Krell et al. BMC Cancer 2012, 12:135
http://www.biomedcentral.com/1471-2407/12/135
Page 2 of 3
of immune cells within human colorectal tumors predict clinical
outcome. Science 2006, 313(5795):1960-1964.
8. Oble DA, Loewe R, Yu P, Mihm MC Jr: Focus on TILs: prognostic
significance of tumor infiltrating lymphocytes in human melanoma.
Cancer immunity: a journal of the Academy of Cancer Immunology 2009, 9:3.
9. Wolf AM, Wolf D, Steurer M, Gastl G, Gunsilius E, Grubeck-Loebenstein B:
Increase of regulatory T cells in the peripheral blood of cancer patients.
Clin Cancer Res 2003, 9(2):606-612.
10. Nedergaard BS, Ladekarl M, Thomsen HF, Nyengaard JR, Nielsen K: Low
density of CD3+, CD4+ and CD8+ cells is associated with increased risk
of relapse in squamous cell cervical cancer. Br J Cancer 2007,
97(8):1135-1138.
11. Matkowski R, Gisterek I, Halon A, Lacko A, Szewczyk K, Staszek U,
Pudelko M, Szynglarewicz B, Szelachowska J, Zolnierek A, et al: The
prognostic role of tumor-infiltrating CD4 and CD8 T lymphocytes in
breast cancer. Anticancer research 2009, 29(7):2445-2451.
12. Rakha EA, Aleskandarany M, El-Sayed ME, Blamey RW, Elston CW, Ellis IO,
Lee AH: The prognostic significance of inflammation and medullary
histological type in invasive carcinoma of the breast. Eur J Cancer 2009,
45(10):1780-1787.
13. Merlo A, Casalini P, Carcangiu ML, Malventano C, Triulzi T, Menard S,
Tagliabue E, Balsari A: FOXP3 expression and overall survival in breast
cancer. J Clin Oncol 2009, 27(11):1746-1752.
14. Horlock C, Stott B, Dyson PJ, Morishita M, Coombes RC, Savage P,
Stebbing J: The effects of trastuzumab on the CD4 + CD25 + FoxP3+
and CD4 + IL17A + T-cell axis in patients with breast cancer. Br J Cancer
2009, 100(7):1061-1067.
15. Denkert C, Loibl S, Noske A, Roller M, Muller BM, Komor M, Budczies J,
Darb-Esfahani S, Kronenwett R, Hanusch C, et al: Tumor-associated
lymphocytes as an independent predictor of response to neoadjuvant
chemotherapy in breast cancer. J Clin Oncol 2010, 28(1):105-113.
16. Rosenberg SA, Packard BS, Aebersold PM, Solomon D, Topalian SL, Toy ST,
Simon P, Lotze MT, Yang JC, Seipp CA, et al: Use of tumor-infiltrating
lymphocytes and interleukin-2 in the immunotherapy of patients with
metastatic melanoma. A preliminary report. N Engl J Med 1988,
319(25):1676-1680.
17. Figlin RA, Thompson JA, Bukowski RM, Vogelzang NJ, Novick AC, Lange P,
Steinberg GD, Belldegrun AS: Multicenter, randomized, phase III trial of
CD8(+) tumor-infiltrating lymphocytes in combination with recombinant
interleukin-2 in metastatic renal cell carcinoma. J Clin Oncol 1999,
17(8):2521-2529.
Pre-publication history
The pre-publication history for this paper can be accessed here:
http://www.biomedcentral.com/1471-2407/12/135/prepub
doi:10.1186/1471-2407-12-135
Cite this article as: Krell et al.: The clinical significance of tumor
infiltrating lymphoctyes in breast cancer: does subtype matter? BMC
Cancer 2012 12:135.
Submit your next manuscript to BioMed Central
and take full advantage of: 
• Convenient online submission
• Thorough peer review
• No space constraints or color figure charges
• Immediate publication on acceptance
• Inclusion in PubMed, CAS, Scopus and Google Scholar
• Research which is freely available for redistribution
Submit your manuscript at 
www.biomedcentral.com/submit
Krell et al. BMC Cancer 2012, 12:135
http://www.biomedcentral.com/1471-2407/12/135
Page 3 of 3


The clinical significance of tumor infiltrating lymphoctyes in breast cancer: does subtype matter?

Krell, J

Frampton, AE

Stebbing, J

Spiral - Imperial College Digital Repository

COMMENTARY Open AccessThe clinical significance of tumor infiltratinglymphoctyes in breast cancer: does subtypematter?Jonathan Krell*, Adam E Frampton and Justin StebbingAbstractTumor infiltrating lymphocytes (TILs) are commonly detected in breast tumors but their bearing on diseaseoutcome is uncertain. The importance of TILs appears to be subtype-specific and varies depending on thehistologic characteristics of the tumor. As our understanding of tumorigenesis is increasing the relevance ofimmunobiology will become apparent.Keywords: Tumor infiltrating lymphocytes, Cancer, ImmunobiologyBackgroundBreast cancer comprises many different subtypes char-acterized by distinguishing factors such as cell type oforigin, grade and molecular specificities such as Ki-67levels and receptor status. In recent years furthermolecular characteristics such as specific protein andmiRNA expression levels have been associated withtumor phenotype [1,2], and it appears that multiplefactors determine prognosis in this disease. Although agreater understanding of cancer cell biology is impera-tive to improving treatment, it has been shown thatvariability in the tumor microenvironment can alsoimpact on outcome. The past 30 years have accumu-lated considerable evidence that tumors can elicit asignificant immune response, and the body’s normaldefence mechanisms can play a key role in promotingor preventing carcinogenesis and tumor spread [3].Tumors are commonly infiltrated by lymphocytes(TILs) and their number and subtype are considered toreflect the host immune response to malignancy [4].The concept of cancer immunobiology appears to bean important one and the possible role of TILs indetermining outcome in breast and other cancersneeds further evaluation.Main textCytotoxic CD8+ and CD4+ Th1 T cells function as themajor anti-tumor lymphocytes predominantly throughthe production of interferon-gamma (IFN-g), whereasinterleukin-6 (IL-6), tumor-necrosis factor (TNF) andIL-23 produced by tumor-associated macrophages(TAM) or myeloid-derived suppressive cells (MDSC) arebelieved to promote tumor formation and growth. Theroles played by TILs such as CD4+ CD25+ Foxp3+ TILs(Tregs) and Th17 cells remains less clear but theyappear to suppress the activity of effector cells includingCD4+ and CD8+ cytotoxic T cells, natural killer cells,natural killer T cells, and B cells [5,6]. This activity maypromote the survival of cancer cells by affording protec-tion from both the innate and adaptive immune systems.Several studies have shown that tumor infiltration byeffector T lymphocytes is associated with favorableprognosis [7,8], but that higher numbers of Tregs areassociated with progression in a variety of malignancies[9,10].The clinical significance of TILs in breast cancerremains controversial and lymphocyte location and sub-type appears to determine outcome. High CD4+ andCD8+ lymphocytic infiltration has been associated withpositive lymph node status as well as worse overall sur-vival [11], but higher relative levels of CD8+ TILs in ERnegative breast cancer correlates with a better prognosis[12]. Infiltration by Tregs correlates with tumor inva-siveness and was shown to represent an independent* Correspondence: j.krell@imperial.ac.ukDepartment of Surgery and Cancer, Imperial College, Hammersmith Hospital,Du Cane Road, London W12 ONN, UKKrell et al. BMC Cancer 2012, 12:135http://www.biomedcentral.com/1471-2407/12/135© 2012 Krell et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative CommonsAttribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction inany medium, provided the original work is properly cited.unfavorable prognostic factor, especially in lymph nodepositive breast cancer [13]. TIL levels have also beenassociated with response to breast cancer therapy. Treglevels were significantly reduced during treatment withtrastuzumab whilst Th17 frequencies were concomi-tantly increased [14] and TIL counts have been shownto represent an independent predictor of response toneo-adjuvant paclitaxel [15].The paper by Droeser and coworkers in this additionof BMC cancer addresses the role of TILs in breast can-cer and particularly focuses on the differential lympho-cyte infiltration between histological subtypes.Furthermore, they utilise an extensive clinical follow-updatabase to correlate TIL number in different tumorcompartments with clinico-pathological features andoutcome data. The study is significant in a number ofways: Firstly, despite being a retrospective study thesample size is large and certainly sufficient for the pur-pose of the analysis. Secondly it addresses issues thathave not previously been reported such as T-cell infil-tration in different histological subtypes and the occur-rence of IL-17+ lymphocytes in breast cancer tissue.They used standard immunohistochemical techniques tostain for TILs in a tissue microarray that included 894ductal and 164 lobular breast cancers and correlatedlymphocyte counts with clinico-pathological parametersand survival. The major findings were that ductal andlobular breast cancers appear to be infiltrated by differ-ent lymphocyte subpopulations and that in ductal can-cers increased CD4+ and FOXP3+ lymphocyteinfiltration was linked to more aggressive histologicalfeatures (such as higher grade and ER-negative status)but in lobular carcinomas lymphocyte infiltration wasnot linked to any clinico-pathological parameters. Inter-estingly, although no prognostic relevance could beattributed to absolute TIL number in either histologicalsubtype, a FOXP3+ to CD4+ ratio of greater than onein ductal carcinoma seemed to represent an indepen-dent favorable prognostic variable. IL-17 lymphocytenumbers were low in both histological subtypes and nosignificant difference between TILs was describedbetween tumor or stroma tissue.DiscussionSo what is the true clinical relevance of the currentstudy by Droeser et al.? It provides further evidence thatevaluating Treg tumor infiltration may be a usefuladjunct to current methods used for staging breast can-cer and may serve as a reliable prognostic biomarker.However the data suggest that it is the relative infiltra-tion of different Tregs rather than absolute number thatis most important in this respect. Furthermore, similarfuture studies in the metastatic setting may demonstratea role for TILs in predicting the behavior of advancedtumors. The study also suggests a possible role for TILsas diagnostic biomarkers as there is a clear difference inlymphoctye infiltration between histological subgroups.This finding may also provide valuable information as tohow variability in immunogenicity is associated with dif-ferent tumors or tumor growth patterns. A greaterunderstanding of the function of TILs within a tumormight also aid in identifying those patients most likelyto benefit from immunomodulatory therapies in breastcancer, a strategy that has been used with varying suc-cess in other tumor types such as melanoma [16] andrenal cell carcinoma [17].ConclusionIn an era when standard prognostic, predictive and diag-nostic parameters are ever changing and the use ofextended molecular fingerprint analyses are increasing,we are continually looking for techniques to further ourunderstanding of tumor biology and improve patientoutcome. Although further work is clearly required tofully establish the importance and potential role of TILsin breast and other malignancies, it seems clear that athorough assessment of the immunobiological status oftumors will go someway to achieving these goals. Therelevance of tumor lymphocyte infiltration cannot beignored but needs to be properly evaluated in largerprospective studies which must encompass the para-meters set out in this and previous studies.Authors’ contributionsJK prepared the main text, discussion and conclusion. AEF prepared thebackground and edited the manuscript. JS supervised the writing of themanuscript and edited the draft.Competing interestsThe authors declare that they have no competing interests.Received: 27 February 2012 Accepted: 3 April 2012Published: 3 April 2012References1. Caprioli RM: Deciphering protein molecular signatures in cancer tissuesto aid in diagnosis, prognosis, and therapy. Cancer Res 2005,65(23):10642-10645.2. Calin GA, Croce CM: MicroRNA signatures in human cancers. Naturereviews Cancer 2006, 6(11):857-866.3. Pandolfi F, Cianci R, Pagliari D, Casciano F, Bagala C, Astone A, Landolfi R,Barone C: The Immune Response to Tumors as a Tool towardImmunotherapy. Clinical & developmental immunology 2011, 2011:894704.4. Mahmoud SM, Paish EC, Powe DG, Macmillan RD, Grainge MJ, Lee AH,Ellis IO, Green AR: Tumor-infiltrating CD8+ lymphocytes predict clinicaloutcome in breast cancer. J Clin Oncol 2011, 29(15):1949-1955.5. Trzonkowski P, Szmit E, Mysliwska J, Dobyszuk A, Mysliwski A: CD4 + CD25+ T regulatory cells inhibit cytotoxic activity of T CD8+ and NKlymphocytes in the direct cell-to-cell interaction. Clin Immunol 2004,112(3):258-267.6. Murakami M, Sakamoto A, Bender J, Kappler J, Marrack P: CD25 + CD4+ Tcells contribute to the control of memory CD8+ T cells. Proc Natl AcadSci USA 2002, 99(13):8832-8837.7. Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pages C,Tosolini M, Camus M, Berger A, Wind P, et al: Type, density, and locationKrell et al. BMC Cancer 2012, 12:135http://www.biomedcentral.com/1471-2407/12/135Page 2 of 3of immune cells within human colorectal tumors predict clinicaloutcome. Science 2006, 313(5795):1960-1964.8. Oble DA, Loewe R, Yu P, Mihm MC Jr: Focus on TILs: prognosticsignificance of tumor infiltrating lymphocytes in human melanoma.Cancer immunity: a journal of the Academy of Cancer Immunology 2009, 9:3.9. Wolf AM, Wolf D, Steurer M, Gastl G, Gunsilius E, Grubeck-Loebenstein B:Increase of regulatory T cells in the peripheral blood of cancer patients.Clin Cancer Res 2003, 9(2):606-612.10. Nedergaard BS, Ladekarl M, Thomsen HF, Nyengaard JR, Nielsen K: Lowdensity of CD3+, CD4+ and CD8+ cells is associated with increased riskof relapse in squamous cell cervical cancer. Br J Cancer 2007,97(8):1135-1138.11. Matkowski R, Gisterek I, Halon A, Lacko A, Szewczyk K, Staszek U,Pudelko M, Szynglarewicz B, Szelachowska J, Zolnierek A, et al: Theprognostic role of tumor-infiltrating CD4 and CD8 T lymphocytes inbreast cancer. Anticancer research 2009, 29(7):2445-2451.12. Rakha EA, Aleskandarany M, El-Sayed ME, Blamey RW, Elston CW, Ellis IO,Lee AH: The prognostic significance of inflammation and medullaryhistological type in invasive carcinoma of the breast. Eur J Cancer 2009,45(10):1780-1787.13. Merlo A, Casalini P, Carcangiu ML, Malventano C, Triulzi T, Menard S,Tagliabue E, Balsari A: FOXP3 expression and overall survival in breastcancer. J Clin Oncol 2009, 27(11):1746-1752.14. Horlock C, Stott B, Dyson PJ, Morishita M, Coombes RC, Savage P,Stebbing J: The effects of trastuzumab on the CD4 + CD25 + FoxP3+and CD4 + IL17A + T-cell axis in patients with breast cancer. Br J Cancer2009, 100(7):1061-1067.15. Denkert C, Loibl S, Noske A, Roller M, Muller BM, Komor M, Budczies J,Darb-Esfahani S, Kronenwett R, Hanusch C, et al: Tumor-associatedlymphocytes as an independent predictor of response to neoadjuvantchemotherapy in breast cancer. J Clin Oncol 2010, 28(1):105-113.16. Rosenberg SA, Packard BS, Aebersold PM, Solomon D, Topalian SL, Toy ST,Simon P, Lotze MT, Yang JC, Seipp CA, et al: Use of tumor-infiltratinglymphocytes and interleukin-2 in the immunotherapy of patients withmetastatic melanoma. A preliminary report. N Engl J Med 1988,319(25):1676-1680.17. Figlin RA, Thompson JA, Bukowski RM, Vogelzang NJ, Novick AC, Lange P,Steinberg GD, Belldegrun AS: Multicenter, randomized, phase III trial ofCD8(+) tumor-infiltrating lymphocytes in combination with recombinantinterleukin-2 in metastatic renal cell carcinoma. J Clin Oncol 1999,17(8):2521-2529.Pre-publication historyThe pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2407/12/135/prepubdoi:10.1186/1471-2407-12-135Cite this article as: Krell et al.: The clinical significance of tumorinfiltrating lymphoctyes in breast cancer: does subtype matter? BMCCancer 2012 12:135.Submit your next manuscript to BioMed Centraland take full advantage of: • Convenient online submission• Thorough peer review• No space constraints or color figure charges• Immediate publication on acceptance• Inclusion in PubMed, CAS, Scopus and Google Scholar• Research which is freely available for redistributionSubmit your manuscript at www.biomedcentral.com/submitKrell et al. BMC Cancer 2012, 12:135http://www.biomedcentral.com/1471-2407/12/135Page 3 of 3

BMC Cancer

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Abstract Tumor infiltrating lymphocytes (TILs) are commonly detected in breast tumors but their bearing on disease outcome is uncertain. The importance of TILs appears to be subtype-specific and varies depending on the histologic characteristics of the tumor. As our understanding of tumorigenesis is increasing the relevance of immunobiology will become apparent.</p

Krell Jonathan

Frampton Adam E

Stebbing Justin

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AH: The prognostic significance of inflammation and medullary histological type in invasive carcinoma of the breast.

AR: Tumor-infiltrating CD8+ lymphocytes predict clinical outcome in breast cancer.

C: The Immune Response to Tumors as a Tool toward Immunotherapy. Clinical & developmental immunology

Croce CM: MicroRNA signatures in human cancers. Nature reviews Cancer

Deciphering protein molecular signatures in cancer tissues to aid in diagnosis, prognosis, and therapy. Cancer Res

et al: Type, density, and location Krell et al.

et al: Use of tumor-infiltrating lymphocytes and interleukin-2 in the immunotherapy of patients with metastatic melanoma. A preliminary report.

Grubeck-Loebenstein B: Increase of regulatory T cells in the peripheral blood of cancer patients. Clin Cancer Res

Jr: Focus on TILs: prognostic significance of tumor infiltrating lymphocytes in human melanoma. Cancer immunity: a journal of the Academy of Cancer Immunology

Low density of CD3+, CD4+ and CD8+ cells is associated with increased risk of relapse in squamous cell cervical cancer.

Mysliwski A:

Tagliabue E, Balsari A: FOXP3 expression and overall survival in breast cancer.

The effects of trastuzumab on

Tumor-associated lymphocytes as an independent predictor of response to neoadjuvant chemotherapy in breast cancer.

Zolnierek A, et al: The prognostic role of tumor-infiltrating CD4 and CD8 T lymphocytes in breast cancer. Anticancer research

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The clinical significance of tumor infiltrating lymphoctyes in breast cancer: does subtype matter?

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