We have here found different presentations of lung cancer patients developing pleural effusion after receiving ICI. Three effusion developmental patterns were identified. Type 1 patients developed massive effusion within one month after initiating ICI treatment, usually within two weeks. The first time cytological examinations of thoracentesis after treatment revealed positive for malignancy in all these patients. Their development of effusion could be interpreted as “pseudoprogression”, because the cytological examinations turned negative in the serial thoracentesis afterwards. Fulminant effusion development was resolved within two months after ICI use.
Most researchers reported survival benefits of pseudoprogression markedly better than that of typical progression10–13. In our study, type 1 patients had longer PFS and OS than those of type 3 and type 2 patients. Some studies reported that the malignant pleural effusion present before anti-PD-1 treatment is associated with shorter PFS and OS14. In our study, if pseudoprogression occurred as type 1 pleural effusion, long-term survival could be achieved. Therefore, ICI should still be considered in patients with malignant pleural effusion.
Kolla et al. reported similar cases in which pseudoprogression was suspected after nivolumab administration2. One patient developing massive pleural effusion had frequent thoracentesis for 8 weeks after nivolumab use. Cytological examination from pleural effusion was positive for malignancy. Nivolumab continued and there was a complete response. No more drainage was recorded after the first two months of therapy. That case shared a similar clinical presentation with our type 1 patients and may be categorized as “type 1” pleural effusion.
Type 2 pleural effusion developed one month after ICI treatment had begun. The time from treatment to first thoracentesis was as long as 25 months (case no.8). It is not surprising that the occurrence of irAEs was delayed, since Nigro et al. reported earlier that late-irAEs (after 12 months) are common (incidence 30.3%) in long responders to ICIs15. The cytology of pleural effusion was never documented positive before or after ICI use so this type was not categorized as pseudoprogression. Thoracentesis was usually infrequent. The exception was an atypical case no.7 who developed massive pleural effusion. Cytological results were variable, with alteration of positive or negative findings of malignancy, and subsequent infection of the effusion was also noted.
We identified those with CD4/CD8 ratios of pleural effusion > = 1.93 were well predicted for their survival. Though the initial CD4/CD8 ratio of patient no.1 (type 1) was only 1.89, serial pleural effusion CD4/CD8 ratios examined showed progressively elevated ratios, with the highest reaching 13.8. It is worth noting that the B cell ratio of pleural effusion was also elevated from 0.4–22.1% in serial analyses (Fig. 2). For such patients presented with the typical type 1 or type 2 pleural effusions with CD4/CD8 ratios < 1.93, serial follow up is recommended, because elevation of the ratio may indicate a good response to the ICI treatment. In type 1 patients, elevated B cell percentage is the feature distinguishing them from types 2 and 3 patients.
Three type 3 patients had initial pleural effusion CD4/CD8 ratios > = 1.93. Patient no.11 and 12 showed partial responses at the primary lesion, but development of new lesions was noted during follow up. No further treatment was given after disease progression due to poor performance status. This challenged the interpretation of OS. Patient no.17 developed pleural effusion 19 months after starting durvalumab medication, and CD4/CD8 and B cell ratios then increased, while cytological results were positive. Nevertheless, the PFS of this patient went up to 18.4 months. Infrequent thoracenteses was performed and there’s no disease progression to the other organs beyond the pleura. Longer follow ups are desirable as the clinical presentation was different from other type 3 patients.
Infiltration of inflammatory cells with CD4 + predominant may contribute to elevated CD4/CD8 ratio in the pleural effusion. Scherpereel et al. evaluated T cell populations in patients with pleural effusion. Their blood CD4/CD8 ratios were 1.6. In healthy subjects, the ratio in pleural fluid is 0.59, compared with higher ratios of 3.8 in patients with pleural metastasis16. Aguiar et al. found CD4/CD8 ratios were similarly higher in malignant pleural effusion than in the peripheral blood (i.e., 3.6 vs 1.4)17. Nieto et al. reported that in patients after diagnosing malignant pleural effusion, their lymphocytes count in the pleural effusion is positively correlated with survival. CXCL10 helps attract lymphocytes in malignant effusion9. Accordingly, in patients with malignant pleural effusion, CD4/CD8 ratio of which is higher than the peripheral blood. This may be a defensive mechanism against cancer, and ICI likely reinforces the mechanism.
Regarding irAEs, cytokines or chemokines in response to ICIs have been studied. Khan et al. reported irAEs patients have initially low levels of CXCL9, 10, 11 and 19, but levels of CXCL 9, and 10 remarkably increase after treatment compared with those patients without irAEs18. Lim et al. found elevations of 11 cytokines in patients with severe irAEs, and even introduced a cytokine toxicity score19. IL-17 and IL-6 levels were reported as biomarkers in predicting irAEs20,21. In our study, we found IL-8 levels in patients with pleural effusion CD4/CD8 ratio < 1.93 were higher than those with ratio > = 1.93. IL-8, a chemokine produced by cancer cells, could play a role in cancer microenvironment. Higher IL-8 levels are correlated with poor prognosis22. Only one patient from the type 1 group has a higher level of IL-17. We also examined several other cytokines including IL-1, IL-2, IL-4, IL-6, IL-12p70, INF-γ, and TNF-α. However, the levels of these cytokines are either under detection limit or demonstrate no significant difference among the three types of patients.
There were several limitations of our study. First, its sample size was small, and was conducted retrospectively in a single medical center. Second, not all patients had their CD4/CD8 ratios determined at the initial thoracentesis. Also, their CD4/CD8 ratios were not determined before ICI treatment nor their ratio in the peripheral blood. Third, 11 of 17 patients received both chemotherapy and ICI, presenting a confounder on response evaluation. However, no patient was lost during follow up and all required clinical information was collected. We are the first to report two distinct types of pleural effusions after ICI use. These two types of patients both had relatively good prognosis. Our study is also the first to use the CD4/CD8 ratio in pleural effusion to predict patient survival after ICI use.
In conclusion, beside pleural effusion due to disease progression (type 3), two distinct effusion types were identified after ICI use: type 1, rapid (develop < 1 month) and massive and type 2, slow (develop > = 1 month) and relative indolent. Both types showed better overall and progression free survival than type 3. Type 1 could be interpreted as pseudoprogression of malignant pleural effusion. CD4/CD8 ratio > = 1.93 in pleural effusion after ICI use is a good predicting factor in PFS. In most patients of types 1 and 2, their CD4/CD8 ratios > = 1.93 in pleural effusion. In those patients presented with typical type 1 or type 2 pleural effusion but with CD4/CD8 ratios < 1.93, serial follow up is recommended because elevating ratio may indicate a good response to ICI.