Preliminary Analysis Of The Clinical And Immune Microenvironment Of Immune Checkpoint Inhibitors Pneumonitis

BackgroundImmune checkpoint inhibitors(ICIs)therapy is a revolutionary new therapy for cancer,which greatly prolongs the survival of patients with cancer.However,ICIs may cause a series of unique immune-related adverse events(irAEs).Immune checkpoints pneumonitis(CIP)is a common and potentially fatal irAE.The incidence of CIP in the large clinical studies was 3%-5%,but was up to 13%to 19%in the real-world studies.The pathogenesis of CIP remains unclear.Studies have shown that ICIs may lead to the activation of cytomegalovirus(CMV).It has also been reported on CMV reactivation after checkpoint inhibitor-induced colitis.Whether CMV activation was involved in the development of CIP is unknown.In addition,previous studies have shown that lymphocytes and inflammatory factors may be related to the development of CIP.However,the role of immune microenvironment in CIP is still unclear.The clinical symptoms,imaging,pathology and prognosis of CIP vary greatly.It is necessary to explore the clinical characteristics of CIP.Part 1.Cytomegalovirus activation as a trigger for immune checkpoint inhibitors pneumonitisObjectiveTo explore the correlation between CMV activation and severe CIP(grade≥3),and further to explore the possible pathogenesis of CIP.MethodsWe retrospectively identifed lung cancer patients treated with ICIs at our institute from January 2016 to May 2020.The association between the development of severe CIP and CMV infection status was analyzed.ReslultsAmong 251 cases analyzed,12 patients with severe CIP were identified.All 12 patients had CMV-IgG-positive.Eleven patients(91.7%)were CMV-DNA-negative.91.7%(11/12)of patients were positive for CMV-pp65,indicating an early reactivation of the virus.The histological features of CMV pneumonia were not found in all available lung tissues(including surgical resection specimen of one patient and lung biopsies in three patients).Except for one patient who received delayed antiviral therapy,the symptoms improved after glucocorticoid combined with antiviral therapy.Part 2.Clinical types of immune checkpoint inhibitors pneumonitisObjectiveTo propose the clinical types of CIP according to the clinical factors,and then guide the individualized treatment of CIP patients.MethodsWe conducted a multicenter retrospective study of patients with lung cancer who developed CIP between February 2018 and August 2020.The clinical characteristics,radiologic features,treatments,and outcomes of CIP were analyzed.ReslultsA total of 55 patients developed CIP and were classified into 3 groups as follows:21 in the pure type(PT)group,14 in the induced type(IT)group,and 20 in the mixed type(MT)group.The incidence of severe pneumonitis was significantly higher in the IT group than in the PT and MT groups(71.4%vs.14.3%vs.50.0%,P=0.002).Antiviral therapy was significantly more frequent in the IT group than in the PT and MT groups.Antibiotic therapy was administered in 23.8%,71.4%,and 80.0%of patients with the PT,IT,and MT,respectively.Patients with the PT had a better tumor response to immune checkpoint inhibitors(ICIs)than those with the other 2 types(overall response rate,78%vs.31%vs.44%,P=0.027).Part 3.Analysis of the immune Microenvironment in immune checkpoint inhibitors pneumonitisObjectiveTo analyze the characteristics of immune microenvironment(IME)of CIP and further explore the mechanism of CIP.MethodsWe collected a cohort of non-small cell lung cancer patients treated with ICIs that included eight individuals with CIP(CIP group)and 29 individuals without CIP(Control group).CIBERSORT and the xCell algorithm were used to evaluate the proportion of immune cells.Gene set enrichment analysis(GSEA)and single-sample GSEA were used to evaluate pathway activity.ReslultsCIBERSORT showed significantly upregulated memory B cells,CD8+T cells,and Ml Macrophages in the CIP group.The number of memory resting CD4+T cells and resting NK cells in the CIP group was also significantly lower than in the Control group.The xCell analysis showed a higher proportion of class-switched memory B-cells and M1 Macrophages in the CIP group.Pathway analysis showed that the CIP group had high activity in their immune and inflammatory response pathways and low activity in their immune exhaustion related pathway.Conclusions1.CMV activation may represent a potentially important trigger for CIP.The early use of glucocorticoid combined with antiviral therapy is pivotal to good prognosis for these patients.2.The clinical types of CIP may favor strategies for treatments and predict the tumor response to ICIs.3.CIP patients developed an inflammatory IME,which is characterized by significantly increased activated immune cells and expression of inflammatory molecules,as well as downregulated immunosuppressive lymphocytes and signaling pathways.