This study found that among patients with NSCLC who received initial ICI monotherapy, the long-term survival group with an OS of ≥ 3 years had a higher intake of seafood and higher pre-treatment serum EPA, EPA/AA ratio, and DHA/AA ratio than the short-term survival group with an OS of < 3 years and that the group with a higher serum EPA/AA ratio had significantly more prolonged OS compared with the group with a lower serum EPA/AA ratio.
Dietary intake of ω-3 PUFAs has been reported to suppress carcinogenesis by inhibiting the inflammatory process, metastasis and tumor proliferation [17]. However, several studies have shown that high intake of ω-6 PUFAs induce progression of cancer development [18, 19]. Thus, the dietary balance between ω-3 and ω-6 PUFAs may be important to determine the roles of PUFAs in carcinogenesis.
Supplementation with fatty acids, especially ω-3 PUFAs, has potentially beneficial effects on immune responses and the maintenance of body weight and skeletal muscle mass in patients with lung cancer [20, 21]. ω-3 PUFAs suppress inflammatory responses and enhance antitumor effects [22, 23]. For example, they reduce blood levels of inflammatory indicators in patients with cancer undergoing radiotherapy. In a mouse model of obesity associated with breast cancer, administration of fish oil in addition to a high-fat diet decreased the levels of inflammatory cytokines tumor necrosis factor-α and interleukin (IL)-6 and increased the levels of the anti-inflammatory cytokine IL-10 [24]. In contrast, ω-6 PUFAs promote inflammation when consumed in excess; conversely, they suppress inflammation, but a consistent view regarding this has not been reached [25]. These results suggest that a diet rich in ω-3 PUFAs may enhance the efficacy of ICI treatment. Recent clinical studies have reported an association between the therapeutic effect of ICI treatment and blood cholesterol and fatty acid levels in patients with cancer after chemotherapy treatment [26].
The efficacy of immunotherapy largely depends on the tumor microenvironment (TME); however, infiltration of regulatory T cells, myeloid-derived suppressor cells (MDSCs), and macrophages (TAMs) into the TME, or under hypoxic conditions, suppresses immune function and reduces the efficacy of immunotherapy [27, 28]. Notably, the ratio of ω-3 vs. ω-6 PUFA, regulates infiltration of TAMs in TME as well as tumor initiation and progression, together, impact overall survival (OS) [29]. For example, in breast cancer-transplanted mice fed cocoa butter, which is high in saturated fatty acids, the differentiation of macrophages (TAMs) around the tumor is promoted, and the ω-6 PUFAs, AA, induce chronic inflammation through the production of various prostaglandins, promote the accumulation of MDSCs, and suppress immune function around cancer [30].
Although eicosanoids derived from AA may inhibit inflammation and enhance T cell activity [31, 32], AA also enhances cancer growth by promoting cell proliferation and angiogenesis and inhibiting apoptosis [33, 34]. In contrast, the ω-3 PUFA DHA suppresses the expression of hypoxia-induced factor 1α, which is related to cancer growth, in breast cancer cells and may inhibit cancer growth by inducing apoptosis in cancer cells [35, 36]. Fish oil also inhibits the immunosuppressive effects of saturated fatty acids via chronic inflammation in the TME [37]. In addition, diets rich in ω-3 PUFAs suppress the function of TAMs to reduce inflammation and improve immune function in cachexic mice with colon and prostate cancers, which are models of low nutrition [38, 39]. Therefore, ω-3 PUFAs may compete with ω-6 PUFAs AA to suppress chronic inflammation and improve immune function in the TME, thereby enhancing the efficacy of immunotherapy [40]. Based on these results, it is inferred that to enhance the beneficial effects of ω-3 PUFAs in fish oil on immune function in patients with cancer, it is necessary to maintain adequate intake of the ω-6 PUFAs AA.
This study found that the high serum EPA/AA ratio group had significantly more prolonged OS after ICI treatment compared with the low serum EPA/AA ratio group. The association between the serum EPA/AA ratio and the risk of death in patients with cancer was demonstrated in the Hisayama study, in which a low serum EPA/AA ratio was associated with an increased risk of death in patients with cancer [41]. However, to the best of our knowledge, this is the first report on the association between treatment efficacy and serum EPA/AA ratio in ICI treatment of patients with cancer. Although more than half of the patients treated with ICI therapy fail, we believe that the serum EPA/AA ratio may be a new biomarker that can be used to evaluate the efficacy of ICI therapy and that treatment to increase the serum EPA/AA ratio prior to ICI therapy could enhance the therapeutic effect of ICI therapy.
In the present study, the short-term survival group had a significantly higher intake of sugar and sweeteners than the long-term survival group. Several cancer cells actively take up glucose in an insulin-independent manner, and the glucose taken up is not oxidatively phosphorylated in the mitochondria, which is known as the Warburg effect, but is produced by the glycolytic system for adenosine triphosphate (ATP) production [42, 43]. This has been shown to produce ATP faster, and increased lactate production may contribute to evasion of the immune system and metastasis in the cancer microenvironment [44]. Epidemiological studies have reported that sugar and fructose intake increase cancer risk. For example, a prospective cohort study of patients with colon cancer reported an increased risk of recurrence or death in patients who consumed more than two servings/day of sugary beverages compared with those who consumed less than two servings/day [45]. However, more studies are necessary to address the relation between sugar intake and ICI treatment in patients with NSCLC.
This study had several limitations. First, the measurement of serum PUFA levels were performed once before the treatment of ICI. Thus, the data may reflect only recent dietary consumption. Second, the sample size was very small, and the statistical power was low. Therefore, studies with more patients will be necessary to further explore our hypotheses. Finally, data on the proinflammatory cytokines produced by tumors were not available for our patients.
In conclusion, pre-treatment seafood intake and the ratio of ω-3 PUFAs to ω-6 PUFAs in the serum (EPA/AA ratio) may be associated with OS after treatment in patients with NSCLC who receive initial ICI monotherapy. These results suggest that the pre-treatment serum EPA/AA ratio may be a new biomarker for predicting treatment response to ICI therapy in patients with NSCLC and that nutritional interventions that increase the pre-treatment serum EPA/AA ratio could improve survival. Future large-scale studies are required to confirm these findings.