Abstract
Analysis of tumor-infiltrating lymphocytes (TIL) in primary human colorectal cancer (CRC) by in situ immunohistochemical staining supports the hypothesis that the adaptive immune response influences the course of human CRC. Specifically, high densities of TILs in the primary tumor are associated with good prognosis independent of other prognostic markers. However, the prognostic role of TILs in metastatic CRC lesions is unknown, as is their role in response or resistance to conventional chemotherapy. We analyzed the association of TIL densities at the invasive margin of CRC liver metastases with response to chemotherapy and progression-free survival in a set of 101 large section samples. High-resolution automated microscopy on complete tissue sections was used to objectively generate cell densities for CD3, CD8, granzyme B, or FOXP3 positive immune cells. A predictive scoring system using TIL densities was developed in a training set and tested successfully in an independent validation set. TIL densities at the invasive margin of liver metastases allowed the prediction of response to chemotherapy with a sensitivity of 79% and specificity of 100%. The association of high density values with longer progression-free survival under chemotherapy was statistically significant. Overall, these findings extend the impact of the local immune response on the clinical course from the primary tumor also to metastatic lesions. Because detailed quantification of TILs in metastatic lesions revealed a strong association with chemotherapy efficacy and prognosis, we suggest that the developed scoring system may be used as a predictive tool for response to chemotherapy in metastatic CRC.
Highlights
While the center of the metastasis often contains large areas of necrosis, making objective evaluations difficult, the invasive margin with its clear border showed a clear heterogeneity of tumor-infiltrating lymphocytes (TIL) densities between patients in this larger patient cohort
We show for the first time a strong association between the local immune cell profile and chemotherapy outcome in colorectal cancer (CRC) liver metastases
This clearly extends the observed role for the immune system in primary CRC into metastatic lesions and further into chemotherapy efficacy
Summary
Metastatic colorectal cancer (CRC) accounts for more than 55,000 deaths per year in the United States alone, with the liver. In 20% of patients, liver metastases can be resected with curative intent [2]. Neoadjuvant treatment can improve resectability, but the majority of the patients have nonresectable liver metastases and receive palliative chemotherapy [3]. Modern chemotherapy regimens include monoclonal VEGF or epidermal growth factor receptor (EGFR) antibodies and lead to objective response rates of around 40% to 60% [4], whereas a large proportion of patients experience treatment-related side effects without any clinical benefit. High densities of TILs were shown to be correlated with an improved survival in patients with primary CRC [9,10,11,12,13,14].
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