Tumor-Infiltrating Lymphocytes in Biopsy Specimens Obtained 7 Days after Starting Chemoradiotherapy for Rectal Cancer Are Predictors of the Response to Chemoradiotherapy

Abstract

<b><i>Background:</i></b> Neoadjuvant chemoradiotherapy (nCRT) followed by total mesorectal excision surgery is a standard treatment for locally advanced rectal cancer (LARC). Tumor-infiltrating lymphocytes (TILs) have been reported to be associated with tumor response; however, this remains to be established. We previously reported that histological changes on biopsy specimens obtained 7 days after starting nCRT are strong predictors of response to nCRT. <b><i>Methods:</i></b> The subjects were 208 patients with LARC who received nCRT. TILs on hematoxylin-eosin staining together with immunohistochemical staining of lymphocyte surface markers including CD3, CD4, CD8, and FoxP3 were performed both on the biopsy specimens before and 7 days after starting nCRT. <b><i>Results:</i></b> The proportions of patients with high densities of CD3+, CD4+, CD8+, and FoxP3+ cells 7 days after starting CRT were significantly lower than the respective values before starting nCRT (<i>p</i> < 0.0001, <i>p</i> < 0.0001, <i>p</i> = 0.0023, and <i>p</i> = 0.0046). In biopsy specimens obtained before treatment, high-density CD4+ cells and FOXP3+ cells were significantly associated with tumor shrinkage rate. High-density FOXP3+ cells were significantly associated with marked tumor regression. In biopsy specimens obtained 7 days after starting treatment, high-density CD4+ cells were significantly associated with marked tumor regression, tumor regression grade 1, and tumor shrinkage rate. High-density FoxP3+ cells were significantly associated with marked tumor regression and tumor shrinkage rate. <b><i>Conclusions:</i></b> In patients who received nCRT for LARC, the evaluations of immunohistochemical staining for CD4+ and FOXP3+ TILs were more intimately related to histological response to CRT and tumor shrinkage rates in biopsy specimens obtained 7 days after starting treatment than in biopsy specimens obtained before CRT.

Tumor-Infiltrating Lymphocytes in Head and Neck Cancer: Ready for Prime Time?

“…The potential of using TILs in preoperative prognostication to predict response to neoadjuvant therapy can be a valuable step towards personalized treatment. In some cancers, biopsies have been successfully used to assess TILs as a predictor of treatment response [69][70][71] and to predict lymph node metastasis [72]. Similar studies in preoperative HNSCC biopsies are warranted.…”

A type I interferon footprint in pre-operative biopsies is an independent biomarker that in combination with CD8 + T cell quantification can improve the prediction of response to neoadjuvant treatment of rectal adenocarcinoma

“…This has also been reported in studies of CRC 10 , 11 , 32–34 . In contrast, other studies have not found a significant correlation between TIL density in pre-operative biopsies and tumor shrinkage after neoadjuvant treatment 12 , 35 . This discrepancy may be due to the different evaluation systems used for TRG, cutoff values set for high and low influx of TILs, size of the cohorts, and/or intracohort dependency in the quantification model.…”

Biomarkers and cell-based models to predict the outcome of neoadjuvant therapy for rectal cancer patients

“…In the same study no correlation of pretreatment CD8 + TILs and survival was detected, while a decrease in CD8/FoxP3 ratio after treatment predicted better overall and progression-free survival. A more recent study comparing pre-treatment and biopsy material obtained from rectal tumours 7 days after irradiation showed that a high density of CD4 + and FoxP3 + cells pre-treatment was significantly associated with tumour shrinkage, and that this link was most pronounced in the 7 day biopsies [112]. The location of CD8 + and FoxP3 + T cells in relation to each other as well as the distance from the tumour cells (stromal vs intra-tumoural) could reflect functionality.…”