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Multicenter Study
. 2014 Jan 21;110(2):489-500.
doi: 10.1038/bjc.2013.639. Epub 2013 Oct 29.

Tumour-infiltrating lymphocytes predict for outcome in HPV-positive oropharyngeal cancer

M J Ward  1 , S M Thirdborough  2 , T Mellows  2 , C Riley  2 , S Harris  3 , K Suchak  4 , A Webb  5 , C Hampton  6 , N N Patel  7 , C J Randall  7 , H J Cox  8 , S Jogai  9 , J Primrose  10 , K Piper  4 , C H Ottensmeier  11 , E V King  12 , G J Thomas  13
Affiliations
Multicenter Study

Tumour-infiltrating lymphocytes predict for outcome in HPV-positive oropharyngeal cancer

M J Ward et al. Br J Cancer. .

Abstract

Background: Human papillomavirus (HPV)-positive oropharyngeal cancer (OPSCC) is associated with improved survival compared with HPV-negative disease. However, a minority of HPV-positive patients have poor prognosis. Currently, there is no generally accepted strategy for identifying these patients.

Methods: We retrospectively analysed 270 consecutively treated OPSCC patients from three centres for effects of clinical, pathological, immunological, and molecular features on disease mortality. We used Cox regression to examine associations between factors and OPSCC death, and developed a prognostic model for 3-year mortality using logistic regression analysis.

Results: Patients with HPV-positive tumours showed improved survival (hazard ratio (HR), 0.33 (0.21-0.53)). High levels of tumour-infiltrating lymphocytes (TILs) stratified HPV-positive patients into high-risk and low-risk groups (3-year survival; HPV-positive/TIL(high)=96%, HPV-positive/TIL(low)=59%). Survival of HPV-positive/TIL(low) patients did not differ from HPV-negative patients (HR, 1.01; P=0.98). We developed a prognostic model for HPV-positive tumours using a 'training' cohort from one centre; the combination of TIL levels, heavy smoking, and T-stage were significant (AUROC=0·87). This model was validated on patients from the other centres (detection rate 67%; false-positive rate 5.6%; AUROC=0·82).

Interpretation: Our data suggest that an immune response, reflected by TIL levels in the primary tumour, has an important role in the improved survival seen in most HPV-positive patients, and is relevant for the clinical evaluation of HPV-positive OPSCC.

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Figures

Figure 1
Figure 1
Kaplan–Meier curves for OPSCC mortality in combined patient cohorts. (A) Kaplan–Meier curves for OPSCC mortality according to HPV status (log-rank test, P<0·001). (B) Immunochemistry (p16) and ISH (HPV) showing an example of an HPV-positive tumour. (C) Kaplan–Meier curves for OPSCC mortality according to abundance of infiltrating lymphocytes (TIL; high, moderate or low; log-rank test, P<0·001). (D) H&E-stained sections showing examples of OPSCC with high and low TIL infiltrates. Tumour islands are arrowed. In TILhigh tumours, lymphocytes fill the stromal compartment and infiltrate into tumour islands. (E) Kaplan–Meier curves for OPSCC mortality stratified according to HPV status and TIL levels. Patients with HPV+/TILlow tumours show similar survival to HPV-negative patients. (F) Immunochemistry showing typical examples of HPV-positive OPSCC with high and low TIL. Tumour is positive for p16, T lymphocytes for CD3.
Figure 2
Figure 2
Receiver-operating characteristic (ROC) curve for 3-year mortality in HPV-positive OPSCC to determine the predictive value of T-cell number and/or subtype. (A) Immunochemistry showing representative example of an OPSCC stained with T-cell markers (CD3, pan T cells; CD4, helper T cells; CD8 cytotoxic T cells; and FoxP3, regulatory T cells). (B) ROC curve for 3-year HPV-positive OPSCC mortality using TIL levels (scored on H+E-stained section), compared with cell counts following immunochemistry for T-cell subtypes (CD3+, CD4+, CD8+, and Foxp3+), including subtype ratios (CD4:CD8, and Foxp3:CD8). Immunochemical quantification did not outperform the simpler scoring method.
Figure 3
Figure 3
T cell gene-set enrichment in HNSCC. Gene-set enrichment analysis of publicly available gene sets describing effector CD8+ T cells. Genes to the left and right of the rank-ordered list are enriched in HNSCC patients with early (survival <3 years, mean 16 months) or late mortality (survival >3 years, mean 49 months), respectively. The rank-ordered list of genes describing effector CD8+ T cells is shown in Supplementary Information.
Figure 4
Figure 4
Receiver-operating characteristic (ROC) curves for 3-year HPV-positive OPSCC mortality. (A) ROC curve for 3-year HPV-positive OPSCC mortality derived from the UHS patient cohort (training set) using a model containing TIL levels, smoking, and T stage. The line of no effect is also shown (dashed; area under the curve (AUROC, 50%). This prognostic model was highly predictive of HPV-positive OPSCC mortality, with an AUROC of 0·87. A cut-off score of −0.945 was selected (circled in the figure) based on this ROC curve (DR, 72.7% FPR ,10.2%) and applied to the PFT/BLT (test) cohort. (B) ROC curve for 3-year HPV-positive OPSCC mortality derived from the PFT/BLT patient cohort (test set) using the predictive model containing TIL levels, smoking, and T stage derived from the UHS training set. The line of no effect is also shown (dashed; (AUROC, 50%)). The cut-off score of  0.945 identified in the training set is circled in the figure. This score was highly predictive of 3-year mortality (AUROC, 0·82), with 66.7% of dead patients testing positive (DR=67%) and 5.6% of alive patients testing positive (FPR=11%). The resultant LR for prediction of 3-year mortality was 11.9.
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