The present study suggests that preoperative LCR can indicate the postsurgical prognosis for patients who undergo resection for IHCC. Furthermore, as LCR was associated with CD8+ TILs, it indirectly reflects local tumor immune activity. This is the first report to find a correlation between a systemic immune marker and CD8+ TILs in patients with IHCC.
LCR is already reported to be a prognostic marker for colorectal, gastric, pancreatic, and breast cancers [17–21]. For patients with IHCC who undergo curative resection, NLR, LMR, PLR, and SII are reportedly significant prognostic factors [4, 9–11]. Many papers have especially suggested NLR as a strong prognostic marker for IHCC. In our result, NLR tended to be a prognostic factor in OS, but not significantly so, whereas LCR was found to be an independent prognostic factor. LCR is the combination of TLC and CRP. CRP is a well-established marker for inflammation. Elevated preoperative CRP level is widely reported to be associated with poor prognosis in various cancers, including IHCC [30–32]. CRP is synthesized by hepatocytes in response to IL-6, TNF and IL-1β, which can activate cancer cell proliferation. CRP may reflect systemic inflammation, and cancer cell proliferation and protection from apoptosis. [33, 34]. TLC also reflect host immune status; several papers have associated low TLC with poor prognosis [35, 36]. Thus, LCR, which is the combination of CRP and TLC, may be stronger prognostic factor than NLR. Low LCR was also significantly associated with high age and longer operation time. TLC can reflect host’s nutritional status. Elderly patients with malignancy easily lose their nutritional status. Since the low LCR group had many advanced stage patients, it was considered that the addition of bile duct reconstruction and lymph node dissection led to the extension of operation time.
However, the mechanism that links LCR to patients’ long-term prognosis has been unclear. In the present study, we focused on the relationship between LCR and TILs, which are indicators of local tumor immunity. TILs have attracted recent attention with the development of immune checkpoint inhibitors. In addition, there were some reports TILs had the relationship between peripheral blood cells, such as TLC and absolute neutrophil count (ANC) [23, 24].
Interestingly, although this study found no significant relationship between LCR and stromal TILs, LCR and CD8+ TILs, specifically, were associated. TILs volume is reportedly correlated with tumor mutation burden (TMB) . TMB is the number of gene mutations cancer cells have, and is associated with predicted immunotherapy response . In breast cancer, which is reported to have relatively high TMB and TILs, patients who have more than 50% TILs are often defined as LPBC; <10% TILs are considered minimal . In the present study, the median TIL percentage in all patients was 0.43% (IQR: 0.26–0.77), which was much lower than for breast cancer. Biliary cancer is also reported to have relatively low TMB . Thus, TILs in IHCC were expected to be low, and our result was consistent with that. Low TIL percentage in IHCC may be why LCR and TILs did not correlate. Furthermore, the TIL evaluation method included all mononuclear cells—not only lymphocyte. As IHCC apparently has low TILs, possibly cells other than lymphocytes were affected.
TILs include various types of lymphocytes, such as CD3+, CD4+, CD8+cells; CD8+ T cells are considered especially important among them. Tumor infiltration by CD8+ T cells has been strongly associated with survival of cancer patients [26, 28]. Yoshida et al. also reported that CRP inhibited proliferation, activation, and function of CD8+ T cells in patients with melanoma . Thus, CD8+ TILs may be more strongly associated with LCR, which is a robust prognostic factor. LCR can reflect not only the inflammatory response and immune-nutritional status, but also local tumor immunity via CD8+ TILs. Therefore, LCR can predict prognosis more accurately than the conventional indicators, such as NLR.
CD8+ TILs reported as the prediction factor of response to chemotherapy or immune check point therapy [26, 41]. Thus, preoperative LCR may predict the response to adjuvant therapy. IHCC has high recurrence rate, not only local recurrence but also intrahepatic recurrence or distant metastasis. Reduced surgery may be tolerated in patients with low LCR to maintain general condition. Furthermore, in patients with low LCR, nutrition and exercise therapy before and after surgery may contribute to improving prognosis.
This study had several limitations. First, it is a retrospective analysis from a single center, with a relatively small study cohort. Second, although lymphocytes come in various types, such as CD3+ or CD4+ lymphocytes, we assessed only CD8+ T cells as most representative type for tumor immunity. A larger study, and an assessment of non-CD8+ lymphocytes are issues for the future.