Patterns of toxicity burden for FDA-approved immune checkpoint inhibitors in the United States

Background Immune-related adverse events (irAEs) are a common phenomenon in cancer patients treated with immune checkpoint inhibitors (ICIs). Surprisingly, the toxicity burdens of these irAEs have not been illustrated clearly. In this study, we analyzed irAEs for seven FDA-approved ICIs in cancer treatment to show the pattern of toxicity burden among cancer patients. Methods irAEs associated with seven FDA-approved ICIs, including three PD-1 inhibitors (cemiplimab, nivolumab and pembrolizumab), three PD-L1 inhibitors (atezolizumab, avelumab and durvalumab), and one CTLA-4 inhibitor (ipilimumab), were analyzed based on data from 149,303 reported cases (from January 1, 2015 to June 30, 2022) collected from the FDA Adverse Events Reporting System (FAERS) public dashboard. Proportions of serious irAEs and correlations with tumor type, age and sex were assessed via R package and GraphPad software. Results irAEs related to anti-PD-1 ICIs required less hospital care resources compared with anti-PD-L1 and anti-CTLA-4 ICIs. Patients treated with pembrolizumab had relatively fewer serious cases. Treatment with ICIs led to the highest probability of serious irAEs in patients with lung cancer. ‘Respiratory, thoracic and mediastinal disorders’ and ‘gastrointestinal disorders’ were the two most common groups of disorders caused by the seven ICIs studied. ‘Cardiac disorders’ was the main type of disorders caused by these ICIs in cancer patients aged 65–85, while ‘reproductive system and breast disease’ was the main type of disorder in cancer patients aged 18–64. ‘Respiratory, thoracic, mediastinal diseases’ and ‘reproductive system and breast diseases’ were the main types of disorders associated with treatment with these ICIs in male and female patients, respectively. Conclusion Tissue and organ toxicities of ICIs are age and sex specific. There are risks of respiratory and urinary system toxicity in male patients and reproductive system toxicity in female patients treated with the ICIs studied. Future studies on the toxicity burden of ICIs should incorporate age and sex differences to better understand the relevance of ICI toxicity burden to human immune function to develop appropriate tumor immune and therapeutic intervention strategies. Supplementary Information The online version contains supplementary material available at 10.1186/s13046-022-02568-y.


Background
Immune checkpoint inhibitors (ICIs) have revolutionized the treatment landscape for multiple cancers, demonstrating effective and durable responses and becoming the standard of care for a variety of malignancies [1]. The Food and Drug Administration (FDA) has approved various ICIs for cancer therapy [2], including programmed death-1 (PD-1) receptor inhibitors (e.g., cemiplimab, nivolumab and pembrolizumab), programmed death ligand-1 (PD-L1) inhibitors (e.g., atezolizumab, avelumab and durvalumab), and cytotoxic T lymphocyte-associated antigen (CTLA-4) inhibitors (ipilimumab) [3][4][5]. Although these ICIs improve patient outcomes in various clinical settings, they pose concomitant risks of immunerelated adverse events (irAEs) [6]. These irAEs are unique, delayed, and long-lasting, and can involve any tissue or organ system [7]. Given the increasing use of ICIs, there has been an increase in the burden of both clinical and financial toxicity. More common irAEs include skin toxicities, colitis, hepatitis, pneumonitis, nephritis, and endocrinopathies (i.e. thyroid abnormalities) [8]. Rare irAEs can have unique clinical presentations that can pose a serious issue if not identified promptly, such as encephalitis, myocarditis, and hematologic toxicities (i.e. hemolytic uremic syndrome). From a financial toxicity standpoint, patients, family members, healthcare systems, and insurance companies experience the significant economic weight of ICI treatment and irAEs [9]. Factors such as increased utilization of ICIs due to their expanding FDA approvals in several cancers, high drug expenses with high out-of-pocket expenditures, and costs associated with managing irAEs (e.g., hospitalizations and the use of biologic agents) all contribute to the exponentially increasing cost of cancer care with ICIs. As ICI prevalence continues to increase with immunotherapy being introduced into earlier stages of disease (neoadjuvant and adjuvant settings) and more combinations with ICIs being developed, clinical and financial toxicity will only become more problematic.
Interrogating irAEs in cancer patients remains to be evaluated systemically. In the present study, we estimated the toxicity burden of seven FDA-approved ICIs by analyzing irAEs among treated patients in the United States. The proportions of total and serious irAEs for each ICI and the proportion of serious irAEs for each ICI by cancer type were calculated. Correlations between tissue or organ disease and patient demographics were also calculated for each ICI. Our comprehensive assessment of irAEs according to the latest data reported by the FDA summarizes the major types of risk factors correlated with irAEs, providing a reference for clinicians to predict the occurrence of irAEs resulting in a timely process in clinical practice.

Cases of irAEs associated with ICI treatment
All cases for this study were obtained from the FDA Adverse Events Reporting System (FAERS) public dashboard (https:// www. fda. gov/ drugs/ quest ions-and-answe rs-fdas-adver se-event-repor ting-system-faers/ fda-adver se-event-repor ting-system-faers-public-dashb oard), and a total of 149,303 cases from January 1, 2015 to June 30, 2022  To assess the tumor-type-specificity of irAEs, correlations between irAEs and age (excluding 0-3 years old) and sex were evaluated for each ICI using R software in 18 tissues or organs (reproductive system and breast, cardiac, musculoskeletal and connective tissue, ear and urinary, respiratory, thoracic and mediastinal, renal and urinary, endocrine, skin and subcutaneous tissue, blood and lymphatic system, psychiatric, immune system, eye, hepatobiliary, gastrointestinal, nervous system, vascular, metabolism and nutrition, and neoplasms benign, malignant and unspecified). All 'tissue or organ disorders' , as the one of the 'reaction groups' , were defined by the Medical Dictionary for Regulatory Activities (MedDRA) (https:// fis. fda. gov/ sense).

Tissue-specific gene expression analysis
To attempt to evaluate irAEs with tumor-type specificity at the gene expression level, the expression levels of PD-1, PD-L1, and CTLA-4 in various tissues or organs (such as brain, heart, lung and skin) from male and female patients were analyzed in the GTEx portal (https:// gtexp ortal. org/ home/ gene/). Gene expression levels were normalized using log10 (TMP + 1).

Statistics
Chi-squared test and case-control studies were used to evaluate irAEs associated with the seven drugs. An OR value > 1 indicated that the drug is a positive factor for irAEs, while OR value < 1 indicated the drug is a negative factor. P < 0.05 represented a statistically significant difference. Data statistics and correlation analysis were performed using the GraphPad prism 9 and R packages (Rmisc, corrplot, ggcorrplot, grDevices and vegan).

Results
irAEs related to pembrolizumab require less hospital care resources and are associated with relatively fewer serious cases Referring to the FDA dataset, all annual irAE cases for each drug were divided into the 7 outcome groups separately (died, disabled, hospitalized, life-threatening, non-serious, required intervention, and other outcomes) (Fig. 1). Here, we calculated the proportion of each outcome group for each individual ICI per year (Supplementary Figure S1). To assess the weight of the individual groups for each ICI, we calculated the average probability of each group for each single drug ( Fig. 2A-C) and found for all drugs that hospitalization was the most common outcome (except for the "other outcomes" group).
The mean rate of hospitalization varied widely among patients treated with PD-1 inhibitors and experiencing irAEs: for instance, the average hospitalization rate for cemiplimab patients was 52.05% (from 48.42% to 70.59%) and was the highest among all irAE cases associated with the seven ICIs, while that for nivolumab was the lowest at 26.3% (21.66%-31.47%) and for pembrolizumab was the second lowest at 27.9% (21.6%-31.77%). The mean hospitalization proportion for the other four ICIs ranged 30% to 45%. The proportion of hospitalizations due to irAEs was significantly lower among patients treated with anti-PD-1 ICIs than with anti-PD-L1 or anti-CTLA4 ICIs (P < 0.05) (Fig. 2D). Therefore, irAEs related to nivolumab and pembrolizumab require less hospital care resources.
To accurately evaluate the severity of irAEs, the proportion of serious irAEs (serious irAEs cases / total irAEs cases) and deaths (deaths / total irAEs cases) was calculated for each drug. All drugs were associated with a high proportion of serious irAEs (cemiplimab, 0.96; nivolumab, 0.91; pembrolizumab, 0.84; atezolizumab, 0.95; avelumab, 0.89; durvalumab, 0.93; and ipilimumab, 0.88), with pembrolizumab having the lowest proportion of serious irAE cases among all seven drugs (Fig. 2E). Next, we calculated the odds ratio value for these seven drugs, and found the OR values for pembrolizumab, atezolizumab and ipilimumab were 0.94 (P < 0.0001), 0.85 (P < 0.0001) and 0.98 (p = 0.57), respectively, while the OR for avelumab was 1 and other three drugs had ORs > 1. However, we noticed that the OR for atezolizumab was less than 1 but its irAEs ratio was high (0.95), and the OR for ipilimumab was 0.98 (< 1) but was not significant (P = 0.057 > 0.05).

Serious irAEs are most common among patients with lung cancer
To evaluate which cancer type was most prone to irAEs with the seven drugs, 13 main cancer types were selected. First, the numbers of total and serious irAEs for each drug were calculated for each cancer type (Table 1 and Fig. 3A and B). For cemiplimab, the numbers of total irAEs (59 cases) and serious irAEs (58 cases) were higher in lung cancer patients than in the other 12 cancers, and the proportion of serious irAEs was 50% among all 13 cancer types (Supplementary Figure S2A). For nivolumab, melanoma (11,602 cases) and lung cancer (11,052 cases) patients were most prone to serious irAEs, with an incidence of 41% and 31%, respectively. Similarly, total and serious irAEs were most common among lung cancer (4,399 cases) and melanoma (6,335 cases) patients treated with pembrolizumab, at 41% and 39%, respectively. For all three PD-L1 inhibitors, the numbers of total and serious irAEs were higher among patients with lung cancer than the other 12 cancers: atezolizumab (49%), avelumab (33%) and durvalumab (87%) (Supplementary Figure S2B). From Fig. 3 and S2C (yellow), we also found that serious irAEs were most common among melanoma (76%) and lung cancer (16%) patients treated with ipilimumab among all 13 cancer types. In summary, patients are most likely to develop serious irAEs with the seven ICIs studied when treated for lung cancer.

Tissue or organ disorders caused by FDA-approved ICIs vary widely by age group
The proportions of tissue or organ disorders for these ICIs varied in different age groups ( Supplementary Figure S3), shown in descending order of irAE rate in the 65-85 age group (left to right). We calculated the correlations between these tissue or organ disorders in patients treated with ICIs ( Fig. 5 and Supplementary Table S1).
For avelumab, the three most common types of disorders among treated patients aged 65-85 were 'psychiatric disorder' (71%, significantly correlated with other disorders except 'metabolism and nutrition disorders'), 'nervous system disorders' (60%, significantly correlated with other disorders except 'ear and labyrinth disorders' and 'metabolism and nutrition disorders'), 'ear and labyrinth disorders' (57%, significantly correlated with 'immune system disorders' and 'neoplasms benign, malignant and unspecified'), while 'reproductive system and breast disorders' (67%, significantly correlated with 'blood and lymphatic system disorders' , 'hepatobiliary disorders' and 'psychiatric disorders'), 'hepatobiliary disorders' (42%, significantly correlated with other disorders expect 'metabolism and nutrition disorders') and 'blood and lymphatic system disorders' (42%, significantly correlated with other disorders except 'ear and labyrinth disorders') were the three most common disorders in patients aged 18-64.
Among patients aged 65-85 treated with durvalumab, the three most common types of disorders were 'metabolism and nutrition disorders' (49%, significantly correlated with other disorders except 'psychiatric disorders'), 'renal and urinary disorders' (48%, significantly correlated with other disorders except 'ear and labyrinth disorders' and 'psychiatric disorders') and 'cardiac disorders' (47%, significantly correlated with other disorders except 'ear and labyrinth disorders' and 'psychiatric disorders').
For ipilimumab, 'cardiac disorders' (49%), 'renal and urinary disorders' (47%) and 'vascular disorders (44%) were the three most common types of disorders (significantly correlated with other disorders expect 'immune system disorders') in patients with age 65-85; and 'reproductive system and breast disorders' (52%), 'hepatobiliary disorders' (47%) and 'ear and labyrinth disorders (45%) were the three most common disorders (significantly correlated with other disorders expect 'immune system disorders') in patients aged 18-64. Taken together, 'cardiac disorders' were the major type of disorder caused by these seven drugs among patients aged 65-85 and 'reproductive system and breast disorders' were the main type of disorder among patients aged 18-64.

'Respiratory, thoracic and mediastinal disorders' is the major type of disorder caused by FDA-approved ICIs in male patients, and 'reproductive system and breast disorders' in female patients
Next, we determined proportion of serious irAEs among total irAEs grouped by 18 tissue or organ disorders and associated with patient sex. (Supplementary Figure S4). Correlations between these disorders were also calculated ( Fig. 6 and Table 3). 'Renal and urinary disorders' was one of the three most common types of disorders in male patients cause by PD-1 inhibitors, and was significantly correlated with 'cardiac disorders' , 'endocrine disorders' , 'hepatobiliary disorders' and 'nervous system disorders' in patients treated with nivolumab, and significantly correlated with 'blood and lymphatic system disorders' and 'endocrine disorders' in patients treated with pembrolizumab (Fig. 6A). 'Reproductive system and breast disorders' was one of the three most common types of disorders (all correlation P value > 0.05) in females treated with nivolumab (37%, none) and pembrolizumab (52%, none). 'Renal and urinary disorders' (59%, none) was the most common disorder caused by atezolizumab in males and was significantly correlated with 'cardiac disorders' (P = 0.021), while 'reproductive system and breast disorders' (60%, P > 0.05) was the most common disorder in females (Fig. 6B). The three most common disorders caused by avelumab were 'ear and labyrinth disorders' (71%, significantly correlated  with 'eye disorder'), 'respiratory, thoracic and mediastinal' (64%, significantly correlated with 'eye disorder') and 'vascular disorders' (64%, significantly correlated with 'nervous system disorder, P = 0.049') in males respectively. 'Reproductive system and breast disorders' (50%, none), 'metabolism and nutrition disorders' (42%, none) and 'immune system disorders' (35%, none) were the three most common disorders in females (no correlation with other disorders, P > 0.05). Among patients treated with durvalumab, 'blood and lymphatic system disorders' (64%, significantly correlated with 'cardiac disorders' , 'metabolism and nutrition disorders' and 'reproductive system and breast disorders'), 'respiratory, thoracic and mediastinal' (61%, significantly correlated with 'eye disorders' , 'musculoskeletal and connective tissue disorders' , and 'nervous system disorders'), and 'reproductive system and breast disorders' (60%, significantly correlated with 'blood and lymphatic system disorders' and 'cardiac disorders') were the three most common disorders in male patients, while 'ear and labyrinth' (52%, significantly correlated with 'gastrointestinal disorders'), 'psychiatric disorders' (47%, none), and 'renal and urinary disorders' (46%, none) were the three most common disorders in females.

Discussion
Cancer immunotherapy attempts to boost the body's own defense mechanism to kill cancer cells and defeat cancer. Over the past few decades, immunotherapy with T cell checkpoint inhibitors has promised to revolutionize cancer therapy [3]. ICIs have offered new hope for cancer patients, especially for those with immunoactive tumors classified as "hot tumors" [20]. However, a major limitation of these therapies is that they are effective in only a subset of patients. Furthermore, the use of ICIs involves a series of related complications, namely, irAEs [21][22][23]. Recent research data revealed that up to 69% of ICI-treated patients develop acute or short-term AEs (13% of which are severe or fatal) and up to 43% of ICI patients display chronic or long-term (lasting three month or longer) AEs [21,24]. It is difficult to identify the current evidence in the literature regarding risk factors or biomarkers for the whole category of ICIs as studies are typically either disease-specific (e.g., lung cancer or melanoma), or ICI drug-specific (e.g., pembrolizumab, ipilimumab), or irAE-specific (e.g., pneumonia or gastritis) [25]. It is extremely important to determine whether the assessment of ICI toxicity is needed to predict the occurrence of irAEs or provide early treatment that can modulate the immune system to obtain lasting antitumor effects [26][27][28][29]. As a new class of targeted anticancer drugs, ICIs target the immune tolerance pathways of tumor cells, such as PD-1, PD-L1 and CTLA-4, to kill tumor cells [30]. Chemokines and their receptors exert essential functions in all aspects of immune processes involved in physiology (hematopoiesis, immune defense and tissue health) and pathophysiology (chronic inflammation, allergy, and cancer), suggesting that irAEs may limit the use of chemokine-based reagents including ICIs in cancer treatment [3]. There is a clear need to understand the pattern of drug response and toxicity for ICIs.
In this study, we focused on interrogating irAEs associated with treatment with seven FDA-approved ICIs. These included three PD-1 inhibitors (cemiplimab, nivolumab and pembrolizumab), three PD-L1 inhibitors (atezolizumab, avelumab and durvalumab) and one CTLA-4 inhibitor (ipilimumab). Treatment of ICIs may cause the acute occurrence or the toxicity of any organ system, producing clinical AEs, which have been widely concerned [31][32][33][34]. There is an urgent need to develop reliable toxicity diagnosis and management methods to meet clinical needs. Few studies have determined tissue or organ-specific irAEs as they are mainly a discrete toxicity caused by the nonspecific activation of the immune system, reversible and easily overlooked [3]. Our data indicated that respiratory and gastrointestinal system toxicity is a common irAE in patients treated with these seven FDA-approved ICIs. It appears that lung cancer patients receiving ICIs are prone to serious irAEs. There are several reasons for this. Firstly, from clinical and research data [35][36][37][38][39], ICIs act as first or second-line treatment for lung cancer, and thus the numbers of lung cancer patients treated with ICIs are higher than in other tumor types. Our data also reveals respiratory system disorders are one of the three most common disorders among irAEs in lung cancer patients with ICIs. For instance, cemiplimab, as a new tumor immunotherapy agent showing anti-tumor activity and an acceptable safety profile, has been reported to improve the overall survival (OS) and progression-free survival (PFS) in advanced non-small-cell lung cancer (NSCLC) [39,40]. However, cemiplimab treatment-related irAEs occur in 50% of NSCLC patients, and are more serious than in other tumors [29,41]. Nivolumab is a secondline treatment for lung cancer [35], and is well tolerated in most patients yet has a wide range of irAEs because of its unique toxicity [42]. Pembrolizumab is a first-line monotherapy ICI improving OS and PFS in lung cancer patients, but grade 3 or worse treatment-related irAEs have occurred [15]. Our data also showed the number and proportion of serious irAEs in lung cancer are higher than in other types of cancers. Pembrolizumab and atezolizumab not only lead to lobular hepatitis in patients, but also result in sclerosing cholangitis, lymphocyte duct damage and granulomatous hepatitis. These agents can interact to cause impaired cellular functions such as CD8 ( +) lymphocytes and macrophages [15]. For avelumab, despite this drug showing good clinical results and an acceptable safety profile in solid tumor treatment, severe irAEs occur [43,44], with respiratory disorders ranking second. 'Respiratory, thoracic and mediastinal disorders' is the leading type of disorder caused by durvalumab. Despite durvalumab showing high efficacy in the treatment of lung cancer, this drug can cause irAEs such as interstitial lung disease [38,45], leading to discontinuation. The three-year OS of nivolumab plus ipilimumab (58%) is higher than that with ipilimumab (34%) [14,37], and acute renal failure, diarrhea, hepatotoxicity, hepatitis, pneumonia, sepsis with acute renal insufficiency and thrombocytopenia are common phenomenon with treatment with these two ICIs [46]. Taken together, respiratory and gastrointestinal system toxicity is among the most common types of irAEs associated with the seven ICIs examined in this study. The human immune system function declines annually with age and disorders among different immune system components are manifest by an enhanced response to autoantigens and decreased defense against microbes and cancer. Signs of "immune system aging" in humans may reduce the safety and efficacy of immune systembased treatment strategies or approaches and may lead to the occurrence of cancer and increased respiratory disease [47][48][49][50]. Huang et al. reported that older patients displayed a higher percentage of pulmonary toxicity when treated with ICIs (anti-PD-1/L1) [51], while another study found that older patients better tolerate treatment with ICIs [52,53]. However, information about the irAEs generated by ICIs, and ICIs in older patients is still relatively limited. In this study, we analyzed the irAEs of seven ICIs across different age groups, including ages 18-64, 65-85 and > 85 years, and focused on irAEs among patients aged 65-85. 'Renal and urinary disorders' and 'cardiac disorders' were the most common types of disorders with these seven ICIs in patients aged 65-85 years. Compared with older patients, 'reproductive system and breast disorders' were the main irAEs caused by ICIs in patients aged 18-64. Age-related changes in the immune system may affect the efficacy and toxicity of ICI drugs [51,54]. Here we demonstrate that patients of age 65-85 are more susceptible to ICI-related renal and urologic toxicity, while those of age 18-64 have more reproductive toxicity.
ICIs appear to more commonly produce respiratory and urinary system toxicity in male patients and reproductive system toxicity in female patients. The immune systems differ significantly between men and women after adolescence, which have profound implications for health and disease [55][56][57]. which are also manifest in the response to ICIs [58]. As immune function changes with age, adult women demonstrate greater inflammation and responsiveness than adult men [20,50]. In general, sex differences in immune responses are more pronounced in young adults, which is also evident in older men and women [50]. In addition, older women are more likely to develop autoimmune diseases than older men, while older men are more prone to develop tumors than older women [50,55,57]. In a variety of immune cells, sex hormones can bind to specific receptors to achieve immune function [59,60]. Chen et al. reported that men are more likely to develop ICI-associated renal toxicity with a longer median time of onset and poor prognosis [59]. Our data revealed that ICIs show greater toxicity in respiratory and urinary systems than in other tissues or organs in men, and more intense reproductive toxicity in women. PD-1, PD-L1 and CTLA-4 are slightly different in male and female tissues, therefore, insight into their pathogenesis and interactions may help in better development of immunotherapy strategies to promote clinical care of patients [49,50]. Moreover, an accurate assessment of the effects of cancer immunotherapy in males and females, and the assessment of the applicability of various tumor models for predicting the sex-dependent success of specific immunotherapies, is crucial [59].
ICIs developed to target immune checkpoint proteins have been successfully used to treat patients with metastatic melanoma, HNC, and NSCLC [61][62][63][64]. A high percentage of cancer patients treated with ICIs has 'respiratory, thoracic, and mediastinal disorders' , suggesting the dysfunction of patients' lungs. The expression levels of immune checkpoint-coding genes may implicate their importance in the corresponding tissues, and inhibiting their expression may lead to functional disturbance of these tissues, which could be a causative factor for organspecific irAEs. By analyzing the GTEx dataset, we found higher levels of genes encoding PD-1, PD-L1 and CTLA in human lung tissues than in other organs. This may explain why lung-irAEs occur more frequently in ICItreated patients. On the other hand, emerging evidence supports the notion that irAEs may be reflective of mechanism-based autoimmune or inflammatory reactions towards the ICI. Previous reports have described that irAEs can prolong OS and PFS by about 6 or 3 months, respectively [65,66]. For example, the presence of overall irAEs was significantly associated with longer OS in melanoma or NSCLC patients treated with nivolumab [67,68] Recently, a retrospective study of 156 patients who were treated with ICIs compared 82 patients with irAEs with 74 patients with non-irAEs, and indicated that PFS and OS in the irAE group were significantly longer than those in the non-irAE group [69]. Judo et al. reported that only low grade irAEs, but not high grade irAEs, are associated with better responses to anti-PD-1 antibodies in non-melanoma patients [70]. These findings suggest that irAEs could be used to predict more favorable clinical outcomes of ICI therapy given that irAEs are managed appropriately. The effect of irAEs on PFS and OS is evident; however, lung-irAEs can occur at a later phase than non-lung-irAEs (skin, endocrine, digestive tract) and seemed not to prolong OS and PFS. To this end, understanding the general aspect of lung-irAE is a critical issue for cancer researchers.
Our data may differ from previously reported data for several reasons. Different data sources may be one cause of discrepancies. For example, Baggi's study analyzed data from 131 advanced and metastatic cutaneous squamous cell carcinoma cases [41], while our study included 492 total irAE cases across 13 common tumors. Another important factor is the difference in statistical objects. The rate of grade 3-4 irAEs was 9.2%, while treatment-related irAEs were seen in 42.7% of the total patients in Baggi's study [41], which is very similar to the data we reported. As for specific ICIs, the rates of grade 3-4 treatment emergent AEs and serious irAEs were 44% and 29%, respectively, in advanced cutaneous squamous cell carcinoma patients with cemiplimab treatment [40], while the rates of grade 3 and 4 irAEs were 13.8% and 73.2%, respectively, in small-cell lung cancer patients treated with nivolumab [71]. These studies were conducted at a single institution with higher or lower medical comorbidities and reported cancer disparities compared to the rest of the country or only for a single ICI. Our current study estimated irAEs of seven FDAapproved ICIs in the United States. For example, the rate of cemiplimab treatment-associated AEs in lung cancer patients was 50% of the total cancer cases reported to the FDA. Thus, the resulting data should be more applicable to preserving quality of life and avoiding or minimizing the risk of irAE-related fatal outcomes.
As the major consequence of ICI treatment, antitumor immunity is activated with infiltration of immune cells, including T cells, into tumors. Increased T cell diversity in response to ICI treatment could also be a sign of immune response to normal tissues. Oh et al. found that initial broadening in the repertoire of circulating T cells occurred within 2 weeks in patients with metastatic castration-resistant prostate cancer treated with a combination of ipilimumab and granulocyte-monocyte colony-stimulating factor, which significantly preceded irAE onset and was correlated with the development of irAEs [72]. To the best of our knowledge, there are few relevant studies reporting the potential association between innate immune cells and irAEs, which will be an interesting research direction in the future.

Conclusions
In summary, our study focuses on the toxicity burden of seven FDA-approved ICIs in 13 common cancers and 18 tissues or organs of patients. ICIs have the highest probability of serious irAEs in patients with lung cancer, which may be associated with the respiratory toxicity of ICIs. Further, the tissue or organ toxicity of ICIs is age-and sex-specific. ICIs are associated with greater renal and urinary system toxicity among patients aged 65-85 years, reproductive toxicity in patients aged 18-64, respiratory and urinary system toxicity in males, and reproductive system toxicity in females. These differences in patients' age and sex should be considered during ICI treatment. Further studies on the toxicity mechanism of ICIs are needed to provide more accurate basic research data for clinical practice.