An increase in peripheral blood CD86-positive plasmacytoid dendritic cells is associated with immune-related adverse events after immune checkpoint inhibitor therapy in patients with non-small cell lung cancer

doi:10.21203/rs.3.rs-1627927/v2

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An increase in peripheral blood CD86-positive plasmacytoid dendritic cells is associated with immune-related adverse events after immune checkpoint inhibitor therapy in patients with non-small cell lung cancer

https://doi.org/10.21203/rs.3.rs-1627927/v2

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Background: The occurrence of immune-related adverse events (irAEs) after immune checkpoint inhibitors (ICIs) is unpredictable. Peripheral blood mononuclear cell (PBMC) profiles, representing host immune status, have potential for predicting irAEs.

Methods: PBMC subsets were measured using multicolor flow cytometry before and at weeks 2 and 8 after the initiation of ICIs in patients with non-small cell lung cancer.

Results: Sixteen evaluable patients were eligible for the analysis. The following irAEs occurred in 6 (37.5%) patients: diarrhea (n = 2), diarrhea and rash (n = 1), pneumonitis (n = 1), pituitary dysfunction (n = 1), and cholangitis (n = 1). Patients with irAEs demonstrated higher levels of CD86⁺plasmacytoid dendritic cells (pDCs) at baseline and weeks 2 and 8 after the ICIs than patients without irAEs (p = 0.005, 0.038, and 0.050, respectively). In patients with irAEs, the levels of CD86⁺pDCs decreased at weeks 2 and 8 compared with baseline (p =0 .034 and 0.025, respectively) but did not change in patients without irAEs. Other PBMC subsets had no significant associations with irAEs. Higher levels of natural killer (NK) cells were significantly associated with overall objective response (p = 0.024).

Conclusions: Higher levels of CD86⁺pDCs at baseline and the reduction at 2 and 8 weeks after the ICIs were associated with the occurrence of irAEs. Higher levels of NK cells were associated with therapeutic efficacy. Measurements of PBMCs may be useful for predicting the efficacy and safety of ICIs.

immunotherapy

immune-related adverse events (irAEs)

immune checkpoint inhibitors (ICIs)

peripheral blood mononuclear cell (PBMC)

CD86+plasmacytoid dendritic cells (pDCs)

Immune checkpoint inhibitors (ICIs) are an important part of cancer therapy. Unlike conventional chemotherapy, which has direct toxicity against tumor cells, ICIs activate anti-tumor immune responses, which provide unprecedented clinical benefits. Treatment of patients with ICIs may result in immune-related adverse events (irAEs), which are defined as a spectrum of side effects that mimic autoimmune diseases (1). ICI treatment can cause irAEs in any organ at any time, making it difficult to predict the occurrence in clinical practice (2).

Assessment of host–tumor interactions and tumor characteristics are essential to understand the modulatory effects of ICIs on the immune system of cancer patients. It has become increasingly evident that the host immune status, assessed by peripheral blood mononuclear cell (PBMC) profiles, is associated with ICIs’ clinical efficacy. For example, higher levels of active natural killer (NK) cells and programmed death-1 (PD-1) positive CD8⁺T cells in peripheral blood are associated with the clinical response to nivolumab, an anti-PD-1 antibody (3). Furthermore, increased NK cells and decreased myeloid-derived suppressor cells are associated with the clinical response to nivolumab (4).

Little is known about the associations between irAEs and PBMCs. The development of irAEs after ICI treatment is likely caused by an-activated immune system. A positive relationship exists between the efficacy of ICIs and irAE development, which suggests common underlying mechanisms (5,6). Because irAEs may represent enhanced immune function, assessment of PBMC profiles may provide useful information for understanding the mechanisms of irAE development. Using advanced multicolor flow cytometric analysis, this exploratory study comprehensively assessed PBMC profiles before and after ICI therapy and analyzed associations between immune cell subsets and irAEs in patients with advanced non-small cell lung cancer (NSCLC).

2.1. Study design

This was an exploratory, prospective observational study conducted in accordance with the ethical standards of the Declaration of Helsinki. The study protocol was approved by the Institutional Review Board of Hamamatsu University School of Medicine (No. 16-080). Each patient provided written informed consent. The study was registered with the University Hospital Medical Information Network Clinical Trial Registry (000026140).

2.2. Patient eligibility

Patients were included in this study if they presented with inoperable stage IIIB or IV NSCLC, had an Eastern Cooperative Oncology Group performance status (ECOG-PS) of 0–2, and were scheduled for anti-PD-1 therapy. Patients who had a history of ICI therapy were excluded. The choice of anti-PD-1 therapy depended on the treating physician and was administered intravenously as follows: nivolumab at a dose of 3 mg/kg every 2 weeks or pembrolizumab at a dose of 200 mg every 3 weeks.

2.3. Treatment and evaluation schedule

Blood samples were collected before and at weeks 2 and 8 after the initiation of anti-PD-1 therapy. Chest computed tomography was performed before and 4 and 8 weeks after the initiation of anti-PD-1 therapy and repeated every 8 weeks until cessation of ICI therapy. The expression of PD-L1 was assessed by Dako 22C3 pharmDx (Agilent Technologies Santa Clara, CA, USA). Adverse events were graded using the Common Terminology Criteria for Adverse Events, version 5.0. Radiological response was evaluated according to the Response Evaluation Criteria in Solid Tumors, version 1.1.

2.4. Measurements of peripheral blood mononuclear cells

A total of 16 mL of peripheral blood samples were collected using two preparation tubes (8mL for each) containing sodium heparin (BD Vacutainer CPT; Becton, Dickinson and Company, Franklin Lakes, NJ, USA). The collection tubes were gently inverted 8 to 10 times to mix anticoagulant with blood. After centrifugation at 1500 × g for 15 min at room temperature, peripheral blood mononuclear cells (PBMCs) were in a whitish layer just under the plasma layer. Then PBMCs were collected with Pasteur pipettes and cryopreserved immediately in CellBanker 1^® medium (Takara Bio Inc., Tokyo, Japan) and stored at −80°C. Aliquots of the frozen PBMCs were suspended in 50 mL phosphate buffered saline (PBS). Then, the 50 mL of fluorescent labeled-surface marker antibody (Supplementary Table 1) with Brilliant Stain Buffer (Becton, Dickinson and Company, Franklin Lakes, NJ, USA) was combined with PBMCs to make a total of 100 mL of cell solution, followed by a 20 min incubation at 4°C. PBMCs were immediately washed once with 2.0 mL of PBS, and after washing, samples were fixed using BD CellFIX (Becton, Dickinson and Company, Franklin Lakes, NJ, USA). At least 50,000 live events were detected using an LSRFortessa^TM X-20 flow cytometer with FACSDiva^TM software (BD Biosciences, San Jose, CA, USA). For analysis of immune cell profile, at the beginning of the gating strategy, the discrimination of single cells from doublets was performed using a forward scatter-area (FSC-A) versus forward scatter-height (FSC-H), followed by using a side scatter-area (SSC-A) versus side scatter-height (SSC-H) bivariate plot. Then, the dead cells were removed using Fixable Viability Dye. All flow cytometric analyses were performed using FlowJo (BD Biosciences). Details of FCM panel and gating strategy are described in Supplementary Figure 1.

Different immune cell populations were analyzed as follows: CD4 ⁺T cells, CD8 ⁺T cells, B cells, monocytes, proinflammatory monocytes, monocytic myeloid derived suppressor cells (mMDSC), myeloid dendritic cells (mDC), CD141⁺ dendritic cells (DCs), plasmacytoid dendritic cells (pDC), basophils, natural killer (NK) cells, minor NK cells, and NK T cells (NKT). To evaluate the activation status, the expression of CD80, CD86, CD274 (PD-L1), and CD273 (PD-L2) was analyzed for each immune cell type. The definitions of immune cell types are described in Supplementary Table 1 and 2. Immune cell populations were expressed as a percentage of PBMCs, and activation status of each immune cell type was expressed as a percentage of the corresponding immune cell population.

2.5. Statistical analyses

The Wilcoxon rank sum test was used to compare CD86⁺plasmacytoid dendritic cell (pDC) levels between the patients with and without irAEs. A p value < 0.05 (two-sided) was considered significant. All values were analyzed using JMP software, version 13.0.0 (SAS Institute Japan, Tokyo, Japan).

3.1. Patient characteristics

From September 2016 to December 2018, 23 patients were enrolled in the study. Of those, 7 patients were excluded from the analysis because of rapid disease progression, which caused early withdrawal from ICI therapy (n = 3), and insufficient PBMC availability (n = 4). As a result, 16 patients had evaluable blood samples before ICI treatment and were eligible for analysis (Table 1). In addition to the baseline samples, 14 and 9 patients had evaluable blood samples at weeks 2 and 8, respectively, after the initiation of anti-PD-1 therapy. Only 1 patient (case 12) had a mutation in the epidermal growth factor receptor gene; the other patients had no oncogenic driver mutations. Eleven (68.8%) patients had positive PD-L1 expression with tumor proportion scores (TPS) ≥ 1% of whom 8 (50.0%) had TPS ≥ 50%. No patients had a history of autoimmune disease, or received systemic steroid therapy or immunosuppressive agents.

3.2. Delivery of ICI therapy

Nivolumab was administered to 10 (62.5%) patients as the second line or later therapy, and pembrolizumab was administered to 6 (37.5%) patients as the first line therapy. An objective response was observed in 9 (56.3%) patients, and 3 (18.8%) and 4 (25.0%) patients had stable and progressive disease, respectively. The median duration of anti-PD-1 treatment was 3.9 months (range: 1.0–18.5 months), and the median observation time was 12.3 months (range: 3.1–24.6 months).

3.3. Developments of irAEs

The development of irAEs was observed in 6 (37.5%) patients (Table 2). The median time to development of irAEs was 44 days (range: 7–133 days). Systemic steroid therapies were delivered to 3 patients, and the patient with pituitary dysfunction received a low-dose mineralocorticoid supplementation. In Case 1, grade 1diarrhea and rash occurred at 7 and 28 days, respectively, which was improved by antidiarrheal and steroid ointment without systemic steroid therapy. In Case 3, grade 3 diarrhea occurred at 23 days after the start of ICI therapy; however, an antidiarrheal was administered first and then oral steroids were initiated at 63 days after the start of ICI therapy (40 days after the development of diarrhea). Thus, no patient received systemic steroids or immunosuppressive agents during the 8 weeks of the study period. No significant associations were observed between the occurrence of irAEs and age, sex, or ECOG-PS.

3.4. Association between CD86⁺pDCs and the developments of irAEs

Compared with 10 patients without irAEs, the 6 patients who developed irAEs demonstrated significantly higher CD86⁺pDC levels at baseline (a median of 3.15% vs. 15.0%, p = 0.005) (Figure 1A). CD86⁺myeloid dendritic cells (mDCs) and the other analyzed PBMC subsets showed no significant associations with the development of irAEs (Figure 1B, Supplementary Table 3). CD86⁺pDCs levels in patients with irAEs were significantly decreased at weeks 2 and 8 after the ICI therapy compared with the baseline values of these patients (p = 0.034 and 0.025, respectively); however, the levels did not change from baseline in patients without irAEs (Figure 2A). Even with decreased levels after the ICI treatment, the patients with irAEs maintained significantly higher CD86⁺pDC levels at 2 weeks (p = 0.038) and a trend toward higher levels at 8 weeks (p = 0.050) compared with those without irAEs (Figure 2A). Decreased proportion of CD86⁺pDC after ICI therapy were observed in all patients with irAEs (except Case 3 who did not have evaluable samples at 2 and 8 weeks after ICI therapy). The time course of CD86⁺pDC in individual cases is shown in Supplementary Figure 2. The representative flow cytometric data for CD86⁺pDCs in patients with and without irAEs are shown in Figure 3. The levels of CD86⁺mDCs and other PBMC subsets did not change at 2 and 8 weeks after the initiation of ICI therapy (Figure 2B). CD86⁺pDC levels had no obvious associations with grade or time to development of irAEs (Supplementary Figure 3-4). Increased proportion of NK cells in PBMCs was significantly associated with the objective response rate (ORR, p = 0.024), whereas the other PBMC subsets and activation status, including CD4⁺T cells, CD8⁺T cells, B cells, CD86⁺pDCs and CD86⁺mDCs, were not associated with the ORR (Figure 4A–F). There was no significant association between CD86⁺pDC levels and age, sex, or ECOG-PS.

In this prospective exploratory study, we comprehensively assessed multiple PBMC subsets in patients with NSCLC who were receiving ICI therapy. We found that the patients who developed irAEs had increased CD86⁺pDC levels at baseline compared with patients who did not develop irAEs. Furthermore, CD86⁺pDC levels in patients with irAEs were significantly decreased by weeks 2 and 8 after initiation of anti-PD-1 therapy. The CD86⁺mDC levels were not associated with irAEs. Additionally, increased proportion of NK cells in PBMCs were associated with the efficacy of ICI. Our data indicate that the assessment of PBMC subsets may aid in predicting the efficacy and safety of ICI therapy.

DCs are a group of antigen-presenting cells that stimulate T cells via co-stimulatory factors, including CD86 (also known as B7-2) (7,8). Among several subsets of DCs, pDCs produce type I interferons (IFN-I) in response to viruses, unlike mDCs which mainly act as conventional antigen-presenting cells (9). Although pDCs constitute only 0.2%–0.8% of PBMCs, emerging evidence suggests that pDCs contribute to the pathogenesis of autoimmune diseases including systemic lupus erythematosus (SLE), systemic sclerosis, psoriasis, autoimmune thyroid diseases, type I diabetes, autoimmune pancreatitis, and inflammatory bowel diseases (IBDs), as well as having a role in immune responses to infectious diseases (10–16). For example, antibody-mediated depletion of pDCs reduced type I interferon responses and disease activity in patients with cutaneous lupus (10). In patients with IBDs, increased numbers of pDCs were observed in inflamed mucosa, and increased levels of peripheral CD86⁺pDCs were associated with disease activity (14). Furthermore, patients with type I diabetes had significantly higher pDC levels in their peripheral blood than healthy individuals (17). Interestingly, autoimmune thyroid disease, IBDs, and type I diabetes are known to occur after ICI therapy. Given the autoimmune aspect of irAEs, it is reasonable to propose that an increase in activated pDCs at baseline may affect the development of irAEs.

The decrease in CD86⁺pDC levels after ICI therapy in patients with irAEs showed another interesting similarity with autoimmune diseases. In patients with type I diabetes, the increased number of peripheral blood pDCs at diagnosis tended to decrease after 2 years, whereas the number of peripheral pDCs was stable over the 2 years in control subjects (17). Additionally, in patients with SLE, psoriasis and autoimmune thyroid diseases, pDC levels were decreased in peripheral blood rather than increased (13,15,18). This seemingly paradoxical behavior is thought to be from an accumulation of pDCs in tissue lesions. In fact, increased pDCs have been observed in involved organs (such as skin, lymph nodes, kidney, or thyroid) in patients with SLE, psoriasis, or autoimmune thyroid diseases (13,15,19). The decrease in circulating CD86⁺pDCs after ICI therapy possibly reflects the recruitment of these cells from the peripheral blood to specific organs.

The accumulation of pDCs in lesional tissues is a common characteristic in several autoimmune diseases; however, controversy exists regarding the levels of circulating pDCs, which were increased in type I diabetes and IBDs, and decreased in SLE, psoriasis, or autoimmune thyroid diseases (13–15,17,19). Although the precise mechanisms involved are unknown, the timing of the evaluation during the course of disease (at diagnosis or after progression) or the specific organs involved may be associated with the differences in circulating pDCs among autoimmune diseases.

The pathogenesis of irAEs and differences in disease pathogenesis among different irAEs are largely unknown. Shared antigens between tumors and organs, inflammation generated by cytokines and activated immune cells, or pre-existing organ inflammation (i.e. autoimmune diseases) might be potential mechanisms (5). The irAEs occur in a wide variety of organs, and therefore, organ-specific mechanisms may exist for each irAE. However, some common mechanisms might also be involved because all the irAEs were caused by autoimmunity triggered by ICIs. As well as having a role in innate immunity by producing IFN-I, pDCs promote the differentiation and maintenance of autoreactive B cells (20,21). Given their multiple roles in innate and adaptive immunity, pDCs might be involved in various irAEs. However, there were no obvious differences in the baseline levels of CD86⁺pDCs among the different types of irAEs. Furthermore, decreased proportion of CD86⁺pDCs were observed after ICI therapy regardless of the type of irAE. These results indicated that pDCs were associated with a common mechanism across irAEs. However, the current study evaluated a limited number and type of irAEs. The organ-specific roles of pDCs should be investigated further.

The association between increased peripheral blood NK cell levels and ICI efficacy has been previously reported and was also observed in the current study (3,22). In animal models, depletion of NK cells attenuated the anti-tumor effects induced by PD-1/PD-L1 blockade. Additionally, PD-1/PD-L1 signaling resulted in reduced anti-tumor activity of NK cells, which was restored after PD-1/PD-L1 blockade (23). The underlying mechanisms are largely unknown; however, these results indicate the considerable importance of NK cells in ICI therapy as a predictive factor of efficacy or therapeutic target.

The current study has four main limitations. First, this was an exploratory study with a limited number of subjects. We evaluated multiple surface markers on immune cells, which may have introduced possible false positives. Furthermore, PBMCs contained a small fraction of pDCs, and therefore, the results of this study should be interpreted with caution. To validate the utility of CD86⁺pDC levels for the prediction of irAE, further studies with larger cohorts will be required. Second, the association between CD86⁺pDC levels and severity or time to onset of irAEs was not evaluated because of the limited number of the patients. Furthermore, irAEs are considered to be results from complex immune responses. Although out data suggested that CD86⁺pDCs play important role in the development of irAEs, it is possible that other unknown factors would associate with the severity or time to onset of irAEs. The differences in pDC function among the organs involved in the irAEs are also unknown. ICI-induced irAEs are a heterogeneous group of conditions that occur in various organs, and the roles of pDCs may differ according to the irAE phenotype. Third, the differences in distribution of immune cells between peripheral blood and organs were not determined. Although circulating CD86⁺pDC levels were not associated with the efficacy of ICI treatment, tumor-infiltrating pDCs likely play an essential role in cancer immunity. In animal models, tumor-infiltrating pDCs induced antitumor immunity by activating NK cells, conventional DCs, and CD8⁺T cells (24). In the tumor microenvironment, tumor-infiltrating pDCs’ anti-tumor activity is attenuated by tumor-derived soluble factors, including transforming growth factor-β, which results in immune tolerance to the tumor (25). Fourth, we only evaluated anti-PD-1 therapy. Several single or combinatorial ICI therapeutic strategies exist, including anti-PD-ligand(L)1 or anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4) antibody therapy, combinations of ICI with chemotherapy, and combinations of ICI antibody therapies. Immune status may differ according to the type of immunotherapy used. In fact, the combination of anti-PD-1 and anti-CTLA-4 therapeutics demonstrated frequent occurrence of irAEs (26,27). CTLA-4 suppresses T cell activity by binding to CD86; therefore, the CD86⁺pDC behavior during anti-CTLA-4 therapy is of interest. Immunotherapies will become more diversified in the near future as new immunomodulating agents emerge. The associations between host immune status and immunotherapy efficacy and safety should be investigated further.

In conclusion, NSCLC patients who developed irAEs had increased CD86⁺pDC levels in their peripheral blood at baseline. These CD86⁺pDC levels were decreased after ICI treatment. Assessment of host immune status by profiling PBMCs may be useful for predicting the efficacy and safety of ICI treatment.

Funding: This research did not receive specific grants from any funding agencies in the public, commercial, or not-for-profit sectors.

Acknowledgments: We thank Susan Zunino, PhD, from Edanz Group (https://en-author-services.edanz.com/ac) for editing a draft of this manuscript.

Conflict of interests:

Dr. Aoki reported receiving grants from Ono Pharmaceutical Co., Eisai Co., Daiichi Sankyo Company, Chugai Pharmaceutical Co., Otsuka Pharmaceutical Co., and Chiome Bioscience Inc. and honoraria for lectures from Bayer Yakuhin outside the submitted work. Dr. Yamada reported receiving honoraria for lectures from Nippon Boehringer Ingelheim, Ono Pharmaceutical Co. and Taiho Pharmaceutical Co. outside the submitted work. No other disclosures were reported.

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Table 1. Characteristics of the patients in this study who presented with non-small cell lung cancer

Case	Group	Age, years	Sex	ECOG-PS	Stage	Pathology	PD-L1: TPS, %	Treatment line of ICI	ICI therapy	Best response
1	irAE	79	Female	1	IV	Ad	Unknown	2nd	Nivolumab	PD
2	irAE	73	Male	1	IV	Ad	≥50	1st	Pembrolizumab	PR
3	irAE	77	Female	1	IV	Ad	≥50	1st	Pembrolizumab	SD
4	irAE	81	Male	0	IV	Ad	≥50	1st	Pembrolizumab	PR
5	irAE	70	Male	1	IV	Sq	0	4th	Nivolumab	CR
6	irAE	56	Male	0	IV	Ad	≥50	3rd	Nivolumab	CR
7	Non-irAE	69	Male	1	IIIB	Ad	≥50	2nd	Nivolumab	PR
8	Non-irAE	67	Male	1	IV	Ad	0	2nd	Nivolumab	PD
9	Non-irAE	48	Male	0	IV	Others	1-49	2nd	Nivolumab	PD
10	Non-irAE	66	Male	0	IV	Ad	1-49	3rd	Nivolumab	PD
11	Non-irAE	41	Male	1	IV	Others	1-49	2nd	Nivolumab	PR
12	Non-irAE	73	Male	1	IV	Ad	0	7th	Nivolumab	SD
13	Non-irAE	69	Male	1	IV	Ad	≥50	1st	Pembrolizumab	PR
14	Non-irAE	77	Male	0	IV	Sq	≥50	1st	Pembrolizumab	CR
15	Non-irAE	65	Male	0	IV	Ad	≥50	1st	Pembrolizumab	CR
16	Non-irAE	58	Female	0	IV	Ad	0	3rd	Nivolumab	SD

Ad, adenocarcinoma; CR, complete response; ECOG-PS, Eastern Cooperative Oncology Group-performance status; ICI, immune checkpoint inhibitor; irAE, immune-related adverse event; PD, progressive disease; PD-L1, programmed death-ligand 1; PR, partial response; SD, stable disease; Sq, squamous cell carcinoma; TPS, tumor proportion score.

Table 2. The clinical courses of six patients with non-small cell lung cancer who developed immune-related adverse events

Case	irAE	Grade	Time to irAE, days	ICI therapy	Treatment for irAE	Outcomes of irAE
1	Diarrhea Rash	1 1	7 28	Continued	Antidiarrheal Steroid ointment	Not improved
2	Diarrhea	2	84	Discontinued	Antidiarrheal	Improved
3	Diarrhea	3	23	Discontinued	Antidiarrheal and oral steroid	Improved
4	Pneumonitis	2	119	Discontinued	Oral steroid	Improved
5	Pituitary dysfunction	3	133	Discontinued	Mineralocorticoid supplementation	Not improved
6	Cholangitis	5	57	Discontinued	Intravenous steroid and immunosuppressant	Not improved/died

ICI, immune checkpoint inhibitor; irAE, immune-related adverse event

No competing interests reported.

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An increase in peripheral blood CD86-positive plasmacytoid dendritic cells is associated with immune-related adverse events after immune checkpoint inhibitor therapy in patients with non-small cell lung cancer

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