With the introduction of ICIs into the clinic brought a fundamental change in the treatment paradigm for lung cancer. Frontier studies have shown that loss of gut microbiota diversity and altered composition can diminish the therapeutic efficacy of ICIs [8, 9]. Wargo JA, et al. [10] analyzed the composition and abundance of fecal bacteria in patients effective on anti-PD-1 therapy and later observed that the gut microbiota may be an important factor influencing anti-PD-1 therapy. In-depth studies on the mechanisms of the gut microbiota-immune system demonstrated that Fecal bacilli upregulate CD8+ T cells and antigen-presenting molecules, and therefore, the flora itself may have an antitumor effect [11].
OA has been shown to affect the diversity and composition of the gut microbiota [5, 12]. The impact of OA use on ICIs may be an area of research that needs to be focused on [7]. In the study of Impact of concomitant drugs, it can be observed that the application of OA is negatively correlated with the efficacy of ICIs [13]. However, in such study, Chinese patients were not included and the relationship between OA and ICIs was not specifically discussed, which challenges the comprehensiveness of relevant research conclusions. Our research has made up for the above defects.
Relevant studies have shown that pain symptoms seriously reduce the quality of life of cancer patients and are considered to be one of the risk factors for the prognosis of patients [14, 15], which may lead to selection bias in this study and affect the reliability of the conclusions. However, Xie et al. [16] observed in a prospective study of 983 patients with advanced cancer in China that perfect analgesia can significantly prolong the total survival time of patients with advanced cancer, so that they can obtain the same total survival time as patients without pain. Similar conclusions have also been reported [17, 18]. In order to avoid bias, a total of 132 patients with advanced lung cancer were enrolled in this study. At the same time, medical records were consulted, and patients with improved analgesia after OA treatment were selected as the intervention group and patients without pain as the control group.
To avoid bias between different tissue types and treatment regimens, we analyzed patients according to their different treatment regimens. A history of OA treatment was observed to be associated with reduced efficacy of ICIs in all groups. This regimen was not analyzed because only 2 patients (only in the non-OA treated group) were enrolled in the anti-EGFR combination ICIs. Existing studies have demonstrated possible signaling crosstalk between EGFR and PD-L1 [19], which may interfere with the efficacy of ICIs, and further expansion of the cohort may help to identify new contraindications to the combination. In the subgroup analysis of included patients, concomitant OA showed a long-lasting negative impact on survival during treatment with ICIs, with reductions in PFS and OS observed in almost every subgroup discussed. This suggests that OA, as a drug that can interfere with the composition of the gut microbiota, may have a long-lasting and profound negative impact on the immune function of the population under discussion.
In our study, the use of ICIs in first line or not did not confound the conclusions. However, in a study of chemotherapy-immune function-ICIs interaction, it was demonstrated that upfront multiline chemotherapy modulates the expression of antigen-presenting molecules, reduces bone marrow mobilization capacity, and interferes with the therapeutic response to subsequent ICIs [20]. Confusingly, studies have shown that chemotherapy may enhance the efficacy of ICIs by upregulating tumor-specific antigen expression [21, 22]. This disagreement may require more in-depth mechanistic studies and larger clinical trials.
To avoid missing risk factors, we further included in the multifactorial analysis of PFS and OS together with the variables identified in the univariate analysis with P < 0.1. In the multifactorial analysis, PS and OA treatment remained risk factors for the prognosis of ICIs treatment in lung cancer patients. Following adjustment for other confounding factors, the concomitant application of OA therapy remained an independent prognostic factor for PFS (HR = 4.994, 95% CI 3.217–7.753, P < 0.001) and OS (HR = 3.618, 95% CI 2.030–6.240, P < 0.001).
It must be acknowledged that there are still limitations in this study. First, as a retrospective cohort study, this study still has a small enrollment and population concentration in the same region, which may be biased, and the results of the subgroup analysis still need to be discussed and analyzed by a larger sample. Also, the inclusion of non-standard treatment patients improves comprehensiveness while limiting the generalization of findings across subgroups, and an expanded cohort may be helpful. In addition, since gut microbial composition is influenced by ethnic, dietary, and geographic differences, the impact of OA treatment in terms of resistance to ICIs may need to be confirmed in a different patient cohort [23, 24]. Second, the effect of OA on gut flora has been reported in some cancers, and its variation in lung cancer and its efficacy on ICIs remains to be further explored. Finally, because patients were not mandatorily tested for tumor PD-1/PD-L1 expression status prior to receiving ICIs, PD-1/PD-L1 status characteristics were not taken into account in the discussion, which may interfere with the comprehensiveness of the study.
It is not feasible to completely avoid OA treatment in clinical practice. Therefore, elucidating the detailed mechanism of OA affecting the efficacy of ICIs in lung cancer and finding appropriate methods to counteract the negative effect of OA on the efficacy of ICIs may be the direction of further research.
In conclusion, through retrospective analysis, this trial demonstrated that ICI is associated with diminished clinical outcomes in patients with OA. It provides a theoretical basis for subsequent extended cohort studies and prospective studies.
