Background
The immune status of the host has been recognized to be correlated with the cancer progression in patients with various types of cancer. Tumor-infiltrating lymphocytes (TILs), which are one of the indicators of host immunity, affect the tumor growth, metastasis and chemoresistance. Regarding the primary tumor, a high density of TILs was revealed to be correlated with better survival rates [
1‐
3], and TILs were reported to be superior to TNM classification as a predictor of the survival in patients with colorectal cancer (CRC) [
2]. In addition, a high density of TILs was also reported to be correlated with a better efficacy of neoadjuvant chemoradiotherapy in patients with locally advanced rectal cancer [
4].
TILs in the metastatic tumor as well as those in the primary tumor were reported to be a useful predictor of the therapeutic outcome, although relatively few reports on TILs in metastatic tumors have been published compared to reports on TILs in primary tumors. A high density of TILs in the metastatic tumor was reported to be correlated with better relapse-free and overall survival rates after resection of the metastatic tumor [
5,
6] and a better chemotherapeutic outcome [
7]. However, the correlation between the local immune status of the primary tumor and that of the metastatic tumor has been unclear.
The aim of this study was to assess the correlation between the local immune status of the primary tumor and that of the metastatic tumor.
Discussion
In this study, the local immune status of the primary tumor was found to be similar to that of the metastatic tumor in relation to the anticancer immunity. According to the evaluation using the HE-stained sections, the density of tumor-infiltrating mononuclear inflammatory cells in the primary tumor was significantly associated with that in the metastatic tumor. Furthermore, according to an evaluation using immunohistochemistry, the density of TIL subsets, such as CD4+, CD8+ and FOXP3+ TILs, in the primary tumor was significantly associated with that in the metastatic tumor. Furthermore, the density of PD-1+, ICOS+ and Granzyme B+ TILs, a marker of immune escape/activation, in the primary tumor was associated with that in the metastatic tumor.
TILs, which reflect the immune response of the host, are a useful biomarker for predicting the survival and therapeutic outcomes in patients with various cancers, including colorectal, breast, lung, gastric and esophageal cancer, and a number of reports on TILs have been published [
11‐
17]. However, most of them concerned the TILs in the primary tumor, and very few reports have examined TILs in the metastatic tumor. As to the reason for this discrepancy in focus, resection of the metastatic tumor is included in the therapeutic strategy in CRC [
18], while resection of the metastatic tumor is not included in the therapeutic strategy in various other types of cancer, such as gastric cancer and pancreatic cancer [
19,
20]. Furthermore, the rate of surgical indication is quite low, even in cases of metastatic CRC [
21]. Therefore, relatively few samples of metastatic tumor have been made available, resulting in markedly fewer reports on the TILs in metastatic tumors than on the TILs in primary tumors.
Control of the metastatic lesion is very important as a factor related to the prognosis in metastatic CRC. The treatment most often used for unresectable distant metastatic tumor is chemotherapy, and the density of TILs was reported to affect the chemotherapeutic effectiveness. Therefore, it is important to grasp the local immune status of the metastatic lesion in patients with unresectable metastatic CRC. However, it is not easy to collect tissue samples of the metastatic lesion with minimal invasion in clinical practice, making it difficult to grasp the local immune status of the metastatic lesion. In this study, the density of TILs in the metastatic tumor was revealed to have no relationships with the number or size of the metastatic tumor but was shown to be similar to the density of TILs in the primary tumor, as in a few past reports [
5]. Furthermore, the activation/suppression status of the lymphocytes in the primary tumor was similar to that in the metastatic tumor. Although it did not apply to all of the markers, some of the activation/suppression marker values (i.e., ICOS and Granzyme B) of the primary tumor were significantly correlated with those of the metastatic tumor. In addition, the PD-1/CD8 ratio—which has been reported to reflect the immunosuppressive status in the cancer microenvironment [
10] in the primary tumor was correlated with that in the metastatic tumor. Thus, it was considered that in addition to the density of the TIL subsets, the activation/suppression status of the lymphocytes of the primary tumor was associated with that of the metastatic tumor. These results supported our claim that the local immune statuses of the primary and metastatic tumors were associated with each other. Thus, the density of TILs in the primary tumor may be a surrogate marker for the density of TILs in the metastatic tumor. The results obtained in this study support the claim that the local immune status of the primary tumor is associated with the efficacy of the chemotherapy, which was reported in our previous report [
22]. It may be possible to predict the chemotherapeutic efficacy on the metastatic tumor by evaluating the density of TILs in the primary tumor, even if the local immune status of the metastatic tumor cannot be evaluated. The evaluation of the density of TILs in the primary tumor may enable clinicians to stratify the patients who can expect the conversion surgery or the patients who need intensive chemotherapy.
In previous reports, the number of the TILs in the primary tumor was reported to be greater than that in the metastatic tumor. In the present study, the median number of TIL subsets in the primary tumor was greater than that in the metastatic tumor. However, a significant difference was found with respect to FOXP3. We considered that this was because of the small number of cases. On the other hand, the comparison of the activation status of the lymphocytes between the primary tumor and the metastatic tumor was not clarified in this study. Both of the activation and the suppression marker values in the primary tumor were greater than those in the metastatic tumor. This is a subject for future analysis.
There are several points to consider in evaluating the density of TILs in the metastatic tumor in this study. First, the patients with disease recurrence after the curative resection of the primary tumor or the patients who underwent two-stage hepatectomy for synchronous liver metastasis were excluded in this study, because the cancer microenvironment, including the local immune status may change with the lapse of time [
23]. That is, in this study, only the patients who underwent concurrent resection of the primary tumor and the metastatic lesion were enrolled. Second, only the patients with no neoadjuvant therapy were enrolled in this study, because the local immune status may change in response to chemotherapy and radiotherapy [
24,
25]. Third, the same organ should be chosen when evaluating the density of TILs in the metastatic tumor, as the density of TILs may differ depending on the metastatic organ [
26]. Therefore, the subjects were limited to the patients with liver metastases in this study.
Several limitations associated with the present study warrant mention. First, we evaluated a relatively small number of patients, and the study design was retrospective. Second, as mentioned in the previous reports regarding TILs, problems such as the heterogeneity and the optimal cut-off value remain unsolved. Third, whether or not all metastatic tumors have a similar immune status remains unclear, as we evaluated only the largest tumor in cases of multiple liver metastases.