With the wide application and development of ICIs, improving their therapeutic efficacy has become an urgent problem to be solved and concerned. Previous studies reported that immunotherapy efficacy is related to HER2 expression, MMR state, EBV state, and PD-L1 expression (Xie, T et al. 2021). However, limited by cumbersome detection protocols and high costs, they are not considered to be perfect predictors. Several studies on ICIs-based combination therapy have demonstrated its significant benefits regardless of PD-L1 expression status, without inducing concomitant side effects and financial burden for the patients (Diem, S et al. 2021; Capone, M. et al. 2021). Therefore, screening clinically convenient and available markers is essential for judging the benefit of the patients before treatment. Peripheral blood parameters, such as white blood cell count, neutrophil absolute value, platelet count and lactate dehydrogenase level, can be used as inflammatory markers to predict the prognosis of some tumors (Laza-Briviesca, R et al. 2021; Peng, L et al. 2020; Klümper, N et al. 2022). However, peripheral blood biomarkers for predicting response to PD-1 inhibitors in Upper GICs patients remain unclear.
In recent years, it has been reported that peripheral blood biomarkers, including LDH, NLR, PLR, and FAR were suggestive indicators for the prognosis of various cancers patients treated with ICIs (Li, L et al. 2021; Ho, W. J et al. 2018; Chen, Y et al. 2021; Lu, S et al. 2020). In addition nutritional status and inflammatory status have prognostic relevance in patients with a variety of cancers (Diem, S et al. 2021). The markers evaluated in the present study (NLR, LDH, PLR and FAR) reflect well the inflammation and nutritional status. In our study, a total of 93 upper gastrointestinal tumor patients treated with ICIs were included retrospectively. Our data revealed that LDH0<194.5,NLR0 < 4.39, PLR0 < 218.7, FAR0<0.13, LDH1<264.5,PLR1<117.2, LDH2<216.5, NLR1 / NLR0 < 1.75 were independently positive predictors of PD-1 inhibitors. Univariate and multivariate analyses also showed that LDH0, NLR0, PLR0, FAR0, LDH1, PLR1, LDH2 are an independent prognostic biomarker for Upper GICs patients exposed to ICIs. Our findings are consistent with previous studies, a retrospective cohort study with 1714 patients examined the association between pretreatment NLR and TMB levels and survival among patients treated with ICI, and found that the patients with NLR-high/TMB-low had the worst prognosis, while those in the NLR-low/TMB-high group had the best prognosis(Valero, C et al. 2021). Chengliang Yuan et al found that high FAR (≥ 0.145) was independent predictors for ORR and independent prognostic factors for PFS and OS. PFS and OS were significantly shorter in the high FAR group than those in the low FAR group(Yuan, C et al. 2022). Furthermore, previous studies have shown that LDH level is a classic inflammatory marker in patients with cancer, widely studied in lung cancer treated with chemotherapy or targeted therapies, as well as in patients with EGFR-mutant NSCLC; LDH has been found to be associated with shorter survival when increased from 1 to 2.5 times ULN. In melanoma, it has a potentially predictive effect on patients treated with PD-1 and CTLA-4(cytotoxic T lymphocyte–associated antigen 4) inhibitors (Capone, M et al. 2018). Interestingly, Diem et al reported that in 66 patients with melanoma treated with PD-1 inhibitors, a greater than 10% increase in LDH was significantly associated with shorter OS, reflecting the potential value of the monitoring these markers(Diem, S et al. 2021). Patients in the low NLR group had a longer survival time than those in the high NLR group, which was consistent with other studies (Bartlett, E. K et al. 2020). Murakami et al. had reported that the median survival times were 9.1 months in the NLR high group and 17.1 months in NLR low group (p < 0:0001) among patients with unresectable GC.
Why NLR is associated immunotherapy outcome may be attributed to the following reasons: inflammatory reactions induced by tumors generate a cancer-related inflammatory microenvironment resistant to the immune monitor. Neutrophils are a systemic inflammatory index because they suppress lymphocytes’ immune activity by producing chemokines and cytokines (Chen, S et al. 2021). This may explain the negative response to immunotherapy when there is a high level of neutrophils. On the other hand, the lymphocyte count represents a measure of lymphocyte infiltration around the tumor tissues, which has already been reported in association with prognosis in solid cancers (Kim, C. G et al. 2021). A lower NLR stands for relative lymphocyte dominance and reflects the unique properties of favorable inflammatory microenvironment for a subsequent antitumor immunologic reaction. Therefore, in view of these considerations, we suggest that patients with low NLR are prone to have better inflammatory responses and prognoses. Thus, careful attention must be paid when PD-1 inhibitors are given to patients with high NLR levels.
Fibrinogen, a molecule produced by the liver in response to cytokine stimulation, could reflect the status of the tumor associated inflammatory response (Coussens, L. M et al. 2002). A high level of fibrinogen was associated with poor prognosis in cancer patients (Chen, P et al. 2002; Ohara, S et al. 2020). It was reported that nutrition as an important determinant of immune response and malnutrition was associated with impaired cell-mediated immunity against tumor progression and metastasis (Alwarawrah, Y et al. 2018). Low serum albumin, which reflects nutritional status, could predict poor prognosis in cancer patients (Pu, D et al. 2021). As a composite indicator, FAR could represent the coagulation system, nutritional status, inflammation of a patient. Therefore, it is reasonable to adopt FAR as prognostic factors in Upper GICs patients treated with ICIs.
There are still some limitations existing in our study. Firstly, this study was only a single center retrospective analysis with small sample size, meanwhile, some bias and confounding factors are inescapable, and Multi-center prospective cohort studies with larger sample sizes are warranted in the future. For instance, too few patients had peripheral blood biomarkers 6 weeks after treatment. Secondly, overall survival was not available for our analysis considering the follow-up time. Thirdly, peripheral blood parameters were influenced by many other factors, which could not be excluded completely. Last but not the least, the immune mechanism of this phenomenon was still unclear and needed further exploration. Nevertheless, our study has provided a simple, convenient and noninvasive biomarker to predict the response to ICIs in Upper GICs patients which may be helpful to develop individualized treatment.