IL8 potently regulates the chemotaxis of human neutrophils and exerts direct protumorigenic effects, including the promotion of angiogenesis, tumor cell dedifferentiation (for example, epithelial–mesenchymal transition) and invasion and/or metastasis(10–12). Elevated serum IL8 is associated with reduced clinical benefit of immune checkpoint inhibitors(13). IL8 is a powerful chemoattractant for neutrophils and other potentially immune-suppressive myeloid leukocytes(14). Early increases in serum IL-8 levels as a strong predictor of poor outcome in small retrospective cohorts of patients with advanced melanoma or non-small-cell lung cancer (NSCLC) who were treated with immune-checkpoint inhibitors, suggesting a link between IL8 expression and ineffective antitumor immune reinvigoration(15). Meanwhile, we also found high serum baseline IL8 associated with irAEs. This may be due to the fact that after receiving immune checkpoint inhibitor, higher levels of serum baseline IL8 are more likely to recruit neutrophils, thereby inducing inflammatory response and immune-related adverse reactions.
As we all know, due to the particularity of the mechanism of immunotherapy, there is a prolonged trailing effect, which means that the extension of immunotherapy time is beneficial to the survival of some patients. Meanwhile, Previous study have shown that with up to 2 years of safety monitoring for some patients, most adverse events occurred within the first 6 months of therapy, and cumulative toxicities were not observed with prolonged drug exposure(16). However, the study also showed that most delayed irAEs occurred in patients continuing anti-PD-1 therapy, suggesting that continued exposure to anti-PD-1 increases the risk of delayed irAEs(17). Some irAEs are high grade, are difficult to manage and can lead to death. As such, ongoing education, close monitoring and prompt management are required on an ongoing basis for all patients who have received anti-PD-1 therapy.
Hepatic metastases diminish immunotherapy efficacy systemically. Hepatic metastases coopt host peripheral tolerance mechanisms to cause acquired immunotherapy resistance through CD8+T cell deletion(18). A cohort study of 95 patients from colorectal cancer with liver metastases showed that the disease control rate was 58.5% (24 of 41) in patients without liver metastasis and 1.9% (1 of 54) in patients with liver metastasis. Findings of this cohort study suggest that patients with MSS metastatic colorectal cancer and without liver metastases may derive clinical benefits from checkpoint inhibitors(19). Immune checkpoint inhibitor monotherapy and combination therapy have made breakthrough progress in advanced non-small cell lung cancer (NSCLC) patients. Furthermore, compared with the overall population, the liver metastases population was an independent prognostic factor for poor immunotherapy response(20). It is well known that patients who respond to ICI tend to develop irAEs(5). Kimimasa present a case of laparoscopic hepatectomy after receiving lenvatinib plus pembrolizumab and developed hypothyroidism and hypopituitarism after surgery, the patient treated with ICIs and responded effectively to ICI therapy before surgery (21). We need to explore whether liver metastasis is associated with the occurrence of irAEs.
In our study, baseline IL2 levels were correlated with irAEs, IL2 is a key mediator involved in T cell proliferation, survival, and differentiation and in terminating T cell responses to maintain autoimmune tolerance, is a growth factor for CD8+T cells and natural killer cells, and is involved in the production of B cell antibodies(22–24). Patients with high baseline IL2 levels will further enhance the body's immune response after receiving immunotherapy, resulting in autoimmune inflammation. IL2 also can activate tumor-specific T cells. With the development of immunotherapy, high-dose IL2 therapy has gradually increased as a combination therapy, and high-dose IL2 therapy may work together with immunotherapy drugs(25). High-dose IL2 therapy is a short-term, controlled course that can be combined with newer immune checkpoint inhibitor drugs and other immunotherapies in development, which may cause additional irAEs(26). The role of IL2 in tumor immunotherapy still needs to be further studied.
Common features of the clinical presentation of the irAEs were that of a systemic inflammatory response as shown/indicated by the significant increase in CRP (which is the downstream molecular product of IL6) from baseline at the time of index irAEs. This is due to increased circulating pro-inflammatory cytokines likely triggered by ICI-induced T-cell stimulation(27, 28). Two studies reported increased level of IL6 after nivolumab treatment was associated with psoriasiform dermatitis in patients with melanoma (29, 30). Additionally, low baseline IL-6 level may use as a predictor for irAEs. Chaput reported low baseline IL-6, IL-8, and sCD25 was associated with colitis related to ipilimumab treatment in melanoma patients (31). And another study showed low baseline IL6 level acted as independent predicted factor for irAEs (P = 0.007)(32). In summary, high baseline level of IL6 was a risk marker for irAEs. Although the pathogenesis of irAEs is yet to be elucidated, it is hypothesized that irAEs are associated with an infiltration of activated CD8+and CD4+ T-cells in the target tissue(27), increased serum levels of inflammatory cytokines (including IL6)(28) (33, 34) and enhanced complement-mediated inflammation(35). Tocilizumab, an mAb binding to the IL6 receptor (IL6R), was a well-tolerated and effective steroid-sparing treatment for management of irAEs(4). Therefore, we enrolled IL6 in our ROC and DCA curves for predicting irAEs risk of cancer patients, our nomogram had the highest diagnostic efficacy and clinical benefits.
As a potential biomarker for immunotherapy, PD-L1 is widely used. It is mainly expressed on tumor cells and antigen-presenting cells. There are two distinct patterns of PD-L1 expression in tumor cells: constitutive expression due to aberrant signaling pathways or chromosomal alterations, and adaptive up-regulation in response to inflammatory factors. However, constitutive PD-L1 expression can also change adaptively with treatment(36). The KEYNOTE042 trial showed that pembrolizumab monotherapy was significantly superior to chemotherapy in advanced NSCLC patients with high PD-L1 expression(37). Of course, in clinical work, we usually choose treatment regimens based on PD-L1 expression status. we enrolled PD-L1 expression in our ROC and DCA curves for predicting clinical response of cancer patients, our nomogram had the highest diagnostic efficacy and clinical benefits.
In some studies, the development of an irAEs while receiving ICI therapy for NSCLC may be positively predictive. A retrospective study noted that patients who developed an irAEs within 6 weeks of starting ICIs experienced significantly improved ORR, median PFS, and median OS(38). A separate analysis noted that for patients who developed an irAEs during ICI treatment, ORR, DCR, median PFS, and median OS were all improved. There was also a nonsignificant trend towards longer OS if the onset of the irAEs was more than 3 months after starting ICI therapy(39).Furthermore, those patients who developed at least two irAEs had improved outcomes compared to patients with a single irAEs, and those with a single irAEs exhibited better outcomes than patients who developed no irAEs(40). These studies performed subgroup analyses on the type of irAEs that exhibited better outcomes and generally cutaneous and endocrinological irAEs performed better.
In the present study, nomogram is widely used which can transform the sophisticated regression equation into an intuitive graph to make the patients’ prediction risk readable. In this study, we developed a nomogram to predict the irAEs risk and clinical response in cancer patients. We also evaluated its predictive ability and clinical utility. Altogether, the nomogram has good performance in predicting the irAEs risk and occurrence of clinical benefit in these patients. To the best of our knowledge, this was the first study that we developed and verified a nomogram that could accurately predict the irAEs risk and occurrence of clinical benefit among these patients. Nevertheless, there are inevitable shortcomings in our research. As for retrospective analysis, it is challenging to collect some variables and follow-up Information by telephone (such as the wrong information, uncooperative contacts). Meanwhile, although we established a nomogram that could effectively predict irAEs risk and clinical response in patients with solid tumors and validated its predictive ability, lacking an independent external validation cohort is a disadvantage for this study. Therefore, multicenter retrospective and well-designed prospective studies are urgently needed in the future to verify the performance.