Abstract
The immune infiltrate within tumors has proved to be very powerful in the prognostic stratification of patients and much attention is also being paid towards its predictive value. In this work we therefore aimed at clarifying the significance and impact of PD-L1 and PD-1 expression on the prognostic value of CD8+ tumor infiltrating lymphocytes (TILs) in a cohort of consecutive patients with primary resected non-small cell lung cancer (NSCLC). Tissue microarrays (TMA) were built using one representative formalin fixed paraffin embedded block for every case, with 5 cores for each block. TMA sections were stained with PD-L1 (clone SP263), PD-1 (clone NAT105) and CD8 (clone SP57). Number of CD8+ cells per mm2 were automatically counted; median, 25th and 75th percentiles of CD8+ cells were used as threshold for statistical clinical outcome analysis and evaluated in patients subgroups defined by expression of PD-L1 and PD-1 within tumors. We found an overall strong prognostic value of CD8+ cells in our cohort of 314 resected NSCLC, especially in PD-L1 negative tumors lacking PD-1+ TILs, and demonstrated that in PD-L1 positive tumors a higher density of CD8+ lymphocytes is necessary to improve the prognosis. Our data strengthen the concept of the importance of the assessment and quantification of the immune contexture in cancer and, similarly to what has been carried on in colorectal cancer, promote the efforts for the establishment of an Immunoscore for NSCLC for prognostic and possibly predictive purposes.
Highlights
Tumor staging has always been performed according to the evaluation of the pathological features defined in the American Joint Committee on Cancer/Union for International Cancer Control (AJCC/UICC) tumor-nodemetastasis (TNM) system [1].the concurrent evaluation of the immune infiltrate within tumors has proved to be very powerful in the stratification of patients within different prognostic groups with higher precision
The clinicopathologic features based on CD8 median expression are shown in Table 1, where it can be seen a clear association between amount of CD8 lymphocytes and PD-L1 expression on tumors cells, as well as a positive correlation with PD1 expression
The median number of CD8 positive lymphocytes, in the PD-L1 negative and positive tumors, was 505 and 813 per mm2 respectively. Considering this different amount of CD8+ lymphocytes in the PD-L1 negative and positive subgroups, the Disease-free survival (DFS) and Overall survival (OS) analysis was performed using both the median (575 per mm2) and the first (300 per mm2) and third (950 per mm2) quartiles as the threshold
Summary
Tumor staging has always been performed according to the evaluation of the pathological features defined in the American Joint Committee on Cancer/Union for International Cancer Control (AJCC/UICC) tumor-nodemetastasis (TNM) system [1].the concurrent evaluation of the immune infiltrate within tumors has proved to be very powerful in the stratification of patients within different prognostic groups with higher precision. As a matter of fact, the “Immunoscore” has reached an advanced stage of development in colon cancer, where the evaluation of the immune infiltrate, namely CD3+ and CD8+ lymphocytes, has been demonstrated to be an important additional parameter to be integrated with the TNM [2]. In this regard, multicenter prospective studies have been undertaken by an international task force with the aim to further implement the use of the Immunoscore with the TNM (designated TNM-I) in clinical practice [3]. In non-small cell lung cancer, different studies have evaluated the prognostic impact of TILs using different approaches and methods in terms of types of cells, compartment, scoring and material [5]
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