The predictive role of PD-L1 expression and CD8+ TIL levels in determining the neoadjuvant chemotherapy response in advanced ovarian cancer.

doi:10.21203/rs.3.rs-4060106/v1

Objective: To analyze how the PD-L1 expression and CD8+ tumor infiltrating lymphocyte (TIL) levels in biopsy samples before neoadjuvant chemotherapy (NAC) can predict chemotherapy response score and survival for advanced high-grade serous ovarian cancer.

Methods: We retrospectively analyzed 45 patients with advanced epithelial ovarian cancer between 2010 and 2018, who had received at least three cycles of neoadjuvant chemotherapy. PD-L1 expression and CD8+ TIL levels were evaluated by immunohistochemical staining in the pre-NAC tumor samples from which the patients had been diagnosed. The post-NACT tissue samples taken during interval debulking surgery (IDS) were used to evaluate the chemotherapy response score (CRS).

Results: Among all the patients, CRS 1 (no response) was found in 8 patients, CRS 2 (partial response) in 28 patients, and CRS 3 (complete response) in 9 patients. A total of 20 (44.4%) patients had high intraepithelial CD8+ TIL levels, and 35(77.8%) patients had high expression stromal CD8 TIL. No statistically significant relationship was found between high and low expression of intratumoral/stromal CD8+ TIL levels with PFS and CRS. The study found that 33(73.3%) patients had high levels of stromal PD-L1 expression and 28(62.2%) patients had high levels of intratumoral PD-L1 expression. In the intratumoral PD-L1 group, patients with low expression had a PFS of 28 months, whereas those with high expression had a PFS of 17 months (p=0.028). Among the patients with high intratumoral PD-L1 expression, 23 (82.1%) patients showed CRS2, 4 (44.4%) showed CRS3, and only 1(3.6%) showed CRS1 (p=0.000). However, high or low expression stromal PD-L1 did not significantly affect PFS and CRS (p=0.928 and p=0.305; respectively).

Conclusions: We found that intraepithelial PD-L1 expression levels in diagnostic biopsy in ovarian cancer can predict the chemotherapy response score in interval debulking surgery.

Ovarian Cancer

Neoadjuvant Chemotherapy

PD-L1

TIL

CRS

One of the most common gynecologic cancers is ovarian cancer, which has a high mortality rate. Approximately 75% of patients are diagnosed at an advanced stage, and the 5-year survival rate is less than 30% [1]. The standard treatment of ovarian cancer consists of extensive surgical staging followed by platinum-based chemotherapy. Despite the recent efforts on new chemotherapeutic regimens and targeted therapies, there has not been a significant increase in survival rates.

Ovarian cancer is defined by a specific tumor microenvironment that disrupts immune surveillance, impairing the immune system's ability to detect and fight against cancer. Various studies indicate that tumor cells activate immunosuppressive mechanisms to evade antitumor immunity. The PD-1/PDL-1 pathway is one of the most well-defined adaptive mechanisms utilized by tumor cells. In tumors, PD-L1 binding to PD-1 on immune cells can impede the effector function of cytotoxic T lymphocytes, leading to immune evasion and tumor progression [2]. Studies have shown that PD-L1 expression is linked to worse outcomes in several types of solid cancers, including melanoma, kidney, and lung cancer [3]. The role of PDL1 in the development and treatment of ovarian cancer is currently not well understood. There is limited data available on how PD-L1 expression affects the prognosis of ovarian cancer, and results are mostly controversial. According to the study by Hamanishi et al., a correlation was found between PD-L1 expression and decreased overall survival in patients with ovarian cancer [4]. In contrast, a recent study found that high levels of PD-1 and PD-L1 expression in cancer cells, as well as PD-1 and PD-L1 mRNA levels, were associated with better outcomes in terms of progression-free and overall survival [5]. On the other hand, another study has found that there is no relationship between the overall survival and the expression of PD-L1 [6]. The reason for the conflicting results could be the lack of standardized immunohistochemistry (IHC) techniques for measuring programmed death-ligand 1 (PD-L1) levels in tissue.

Primary debulking surgery (PDS) has been the only ovarian cancer treatment with a proven survival advantage since it was established in the 1970s. The existing literature suggests that for certain patients with extensive disease that cannot be effectively removed through surgery, or those who are not good candidates for it, interval debulking surgery (IDS) may be a suitable alternative to PDS after neoadjuvant chemotherapy. All patients, particularly those in these categories, should be evaluated for IDS [7]. The chemotherapy response score (CRS) evaluates the histological impact of neoadjuvant chemotherapy on ovarian cancer and the complete pathological response was significantly associated with improved survival [8]. Although previous studies have shown that various clinical variables, including CA125 and HE4, can be used as prognostic indicators for patients with high-grade serous carcinoma (HGSC) who receive neoadjuvant chemotherapy there are still unmet needs in terms of predictive markers that can precisely identify which patients are more likely to have good responses to NACT and achieve a better CRS[9].

The potential of using markers including PD-L1 and CD8+ TILs in cancer tissues to predict the response to neoadjuvant chemotherapy is being investigated in recent studies. Qi Du et al.'s meta-analysis demonstrated that breast cancer patients with higher PD-L1 expression had a notably greater pathological complete response to neoadjuvant chemotherapy [10]. The high baseline TILs are also associated with increased pathological complete response (pCR) probability [11]. The majority of research on this topic has been conducted on breast cancer patients. However, there is insufficient data to determine a relationship between PD-L1 expression, TIL levels, and neoadjuvant chemotherapy response in ovarian cancer.The purpose of this article is to assess this relationship.

We retrospectively analyzed 45 patients with epithelial ovarian cancer who attended Hacettepe University Hospital between 2010 and 2018. The study was approved by the Hospital's Research Ethics Committee (KA 19101). An 'Informed Consent Form' was obtained from the patients. Demographic and clinicopathological data of the patients were collected using hospital medical records. The stage was evaluated according to the International Federation of Gynecology and Obstetrics (FIGO).

PD-L1 expression and CD8 TIL level evaluations were performed in tissue samples taken via laparoscopy before NACT. Post-treatment tissue samples were obtained through IDS and evaluated for CRS.

Immunohistochemistry staining and interpretation of PD-L1 expression

Three sections were taken from the paraffin blocks of the patients and placed into separate slides with a thickness of 4 µm. One of these sections was stained with Hematoxylin and Eosin (H&E) in order to confirm tissue diagnosis. The other two sections were then stained with CD8+ and PD-L1, according to Leica Bond-Max staining protocols.

CD8 + score; Immunohistochemical staining was performed using a primary antibody (product code Leica NCL-L-CD8+-295, mouse monoclonal antibody, clone 1A5, Newcastle, UK) at a dilution of 1:50. It was evaluated separately for tumor cells and stroma. An area in the stroma that showed a high CD8+ staining was chosen. Using the 40X magnification area of the Nikon Eclipse E200 brand microscope, CD8+-stained lymphocytes were counted in this area and its surrounding areas, and the mean values were calculated. The expression of CD8+ in the stroma was categorized into five groups according to the intensity of the staining as follows: score 0 (average lymphocyte count is 0), score 1(average lymphocyte count is 1-2), score 2 (average lymphocyte count is 3-19, figure1A), score 3 (average lymphocyte count is 20-50), score 4 (average lymphocyte count> 50,figure 1B. Expression of score 3 and score 4 was considered high[12].

The expression of CD8+ in the tumor cells was categorized into three groups. Score 0 (no positive cells), score 1 (only a few positive cells, figure 1C), score 2 (many positive cells, figure 1D). Expression of score 2 was considered high.

PD-L1 score; Immunohistochemical staining was performed using a primary antibody (product code Leica PA0832, rabbit primary antibody, clone 73-10, Newcastle, UK) at a dilution of 1:400. Tumor and stroma were evaluated separately. Only membranous staining was considered positive. Using the 20X magnification of the Nikon ECLIPSE E200 brand microscope, we evaluated the area occupied by PD-L1 positive cells in the tumor and stroma. This area was divided by the total area of the tissue and multiplied by 100 to determine the percentage of staining (Figure 3). Immunohistochemical expression for PD-L1 was analyzed semi-quantitatively in 5% increments, scoring positive cells from 0% to 100% of the total number of cells. The percentage of positive tumor cells in an entire section was determined by two gynecological pathologists without access to patient IDs or clinicopathological data. Any inconsistencies between the two pathologists were eliminated by consensus. It is important to note that there is no established standard cutoff for PD-L1 positivity in ovarian cancer. Some studies define a tumor as PD-L1 positive if positive staining is observed in >1%, >5%, or >10% of the cells [13]. In our study, the PD-L1 expression was categorized into two groups: high expression (PD-L1 ≥ 1%, figure 1E), and low expression (PD-L1 < 1%).

Chemotherapy response score evaluation

The Chemotherapy Response Score (CRS) was used to evaluate the histopathological response to neoadjuvant chemotherapy. The College of American Pathologists and the International Collaboration on Cancer Reporting have used a 3-tier Chemotherapy Response Score (CRS) [14]. The criteria are given below:

CRS score 1: Mainly viable tumor with no or minimal regression-associated fibroinflammatory changes, limited to a few foci; cases in which it is difficult to decide between regression and tumor-associated desmoplasia or inflammatory cell infiltration

CRS score 2: Appreciable tumor response amid viable tumor that is readily identifiable. The tumor is regularly distributed, ranging from multifocal or diffuse regression-associated fibroinflammatory changes with a viable tumor in sheets, streaks, or nodules to extensive regression-associated fibroinflammatory changes with a multifocal residual tumor, which are easily identifiable.

CRS score 3: Complete or near-complete response with no residual tumor OR minimal irregularly scattered tumor foci seen as individual cells, cell groups, or nodules up to 2 mm maximum size. Mainly regression-associated fibroinflammatory changes or, in rare cases no or very little residual tumor in the complete absence of any inflammatory response. It is advisable to record whether there is no residual tumor or whether there is a microscopic residual tumor present.

Statistical analysis:

Statistical analyses were performed using the SPSS package program (IBM SPSS Statistics 23). Fisher's exact test was used to analyze categorical variables. Survival functions were evaluated using the Kaplan-Meier method, and the difference in survival was compared using the log-rank test. The correlation between two variables was evaluated using Spearman's rank correlation coefficient (rho). A statistically significant effect was determined if the p-value was less than 0.05 unless otherwise stated.

A total of 45 female patients with ovarian cancer were included in the study, with a mean age of 61.60 ± 9.94 years. (range: 42–82 years). Of 45 patients, 32 (71.1%) were stage III, and 13 (28.9%) were stage IV at the time of diagnosis. High-grade ovarian cancer was detected in 41 (91.1%) patients, and the grade could not be determined in the remaining 4 (8.9%) patients. In terms of chemotherapy response scores, CRS 1 was found in 8 (17.8%) patients, CRS 2 in 28 (62.2%) patients, and CRS 3 in 9 (20.0%) patients. Out of all the patients, only 4 received five or six courses of NACT due to disease progression after a radiological evaluation, while the remaining 41 patients received a total of three courses of NACT. These 4 patients were evaluated as CRS 1 and the grade of these patients is unknown. Recurrence was observed in 21 (46.7%) of 45 patients, and exitus developed in 6 patients (13.3%). The defined follow-up period from the date of diagnosis to the last follow-up or the date of death of all patients was 19 months. The median progression-free survival (PFS) of the group was 18 months. Baseline characteristics of patients are summarized in Table 1.

Table 1. Demographic and Clinical Features of Patients

PD-L1 expression and patient prognosis

Patients with high levels of intratumoral PD-L1 expression had a lower PFS of 17 months compared to those with low PD-L1 expression, who had a higher PFS of 28 months (p=0.029). However, there was no significant relationship found between stromal PD-L1 levels and PFS, as both groups had similar PFS of 20 and 17 months (p=0.928) (Figure 2A,B and Supplementary Table 2A).

CD8+ TIL expression and patient prognosis

No statistically significant relationship was found between high and low expressions of intraepithelial and stromal CD8+ levels and PFS (p = 0,243 and p =0,805; respectively) (Figure 2C,D and Supplementary Table 2B).

PD-L1 expression and Chemotherapy Response Scoring

Of all the patients, 28 (62.2%) showed a high level of intratumoral PD-L1 expression (PD-L1 ≥ 1%), and 33 (73.3%) exhibited high stromal PD-L1 expression (PD-L1 ≥ 1%). We found that as the level of PD-L1 expression increased in both areas, there was a correlated increase in the number of patients with CRS2 and CRS3 and a decrease in the number of patients with CRS1 (Table 3A). Of the patients with high intratumoral PD-L1 expression, 23 patients experienced CRS2, 4 patients experienced CRS3, and only 1 patient experienced CRS1 (p=0.000). These results showed that there is a significant relationship between intratumoral PD-L1 expression and chemotherapy response scoring. Chemotherapy response was significantly increased in patients with high PD-L1 levels. Although the CRS2 and CRS3 levels tend to increase with high stromal PD-L1 levels, this was not found to be statistically significant (p=0,305) (Figure 3A, B).

CD 8 expression and Chemotherapy Response Scoring

As a result of the IHC evaluation high expression intraepithelial CD8+ TIL levels were observed in 20 (44.4%) patients and high stromal CD 8+TIL expression in 35 (77.8%) patients (Table 3B). It was shown that there was no relationship between intratumoral and stromal CD8+ TIL levels and chemotherapy response score (p=0,303 and p=0,396; respectively) (Figure 3C, D).

Table 3A. Distribution of CRS According to Intratumoral and Stromal PD-L1

Intratumoral PD-L1		CRS 1	CRS 2	CRS 3	Total	p
	Low expression	7(41.2%)	5(29.4%)	5(29.4%)	17(37.8%)	0,000
	High Expression	1(3.6%)	23(82.1%)	4 (44.4%)	28(62.2%)
Stromal PD-L1
	Low Expression	4(33.3%)	6(50.0%)	2(16.7%)	12(26.7%)	0,305
	High Expression	4(12.1%)	22(66.7%)	7(21.2%)	33(73.3%)

Table 3B. Distribution of CRS by Intratumoral and Stromal CD8+ TILs

Intraepithelial CD8 + TILs		CRS 1	CRS 2	CRS 3	Total	p
	Low expression	6 (24.0%)	13 (52.0%)	6 (24.0%)	25(55.6%)	0,303
	High Expression	2(10.0%)	15(75.0%)	3 (15.0%)	20(44.4%)
Stromal CD8+ TILs
	Low expression	3(30.0%)	6(60.0%)	1(10.0%)	10(22.2%)	0,396
	High Expression	5(14.3%)	22(62.9%)	8(22.9%)	35(77.8%)

Identifying new therapeutic targets and biomarkers is an important area of research for oncogenesis and the progression of ovarian cancer. Previous research has demonstrated that the presence of PD-L1 and TILs could be used to predict the outcome of ovarian cancer. According to some studies, the presence of both tumor PD-L1 expression and intraepithelial CD8+ TILs infiltration are prognostic factors for patients with HGSC [4, 15]. Patients with higher PD-L1 expression in tumor cells have been shown to have significantly worse prognoses than those with lower expression. In addition, it is shown that as the CD8+ TILs ratio increased, the patients' survival significantly improved. There are also studies in the literature showing that CD8+ TILs before neoadjuvant chemotherapy do not have a prognostic impact on ovarian cancer[16, 17]. Our study showed that lower PD-L1 expression levels were associated with reduced survival rates, which is consistent with the findings of Hamanashi et al [4]. We determined that patients with low-expression intratumoral PD-L1 (PD-L1 <1%) had a greater progression-free survival than those with high-expression PD-L1 (PD-L1 >1%). Tumor cells are thought to be protected from the immune system by increased expression of PD-L1, allowing tumor cells to rapidly progress [2]. We could not demonstrate a correlation between CD8+ TILs and progression-free survival. We believe that this may be related to the relatively small number of our patients. As our follow-up time is short, we do not have overall survival data. We think that the overall survival relationship with CD8+ TILs should be re-analyzed in our patients with a longer follow-up period.

Recent studies have demonstrated that the tumor microenvironment not only affects a patient's overall prognosis but also their response to conventional anti-cancer medications. In the study of Bohm et al., the densities of CD8+ T-cells and CD45RO+ memory cells did not change in the tumor microenvironment following NACT; however, there was a notable decrease in the number of T regulatory (Treg) cells. Furthermore, PD-1, CTLA4, and PD-L1 expression significantly increased with neoadjuvant chemotherapy. According to a study, patients who responded well (CRS3) to NACT showed higher T-cell activation and less Treg cell infiltration in omental metastases biopsies than those who had a poor response (CRS2) [14]. Mesnage et al.analyzed the levels of PD-L1 and TILs in paired pre- and post-NACT samples. It was found that chemotherapy led to an increase in the level of PD-L1 and iTILs/TILs. Both pre- and post-NACT high levels of sTILs were found to be prognostic factors for PFS. The study did not find any significant impact of ieTILs or PD-L1 expression on prognosis [16]. In contrast, the study of Kim et al.indicated that PD-L1 and TIL in residual tissue following neoadjuvant chemotherapy did not have an impact on survival. The effect of NAC on the expression of PD-L1 and stromal TILs varied significantly among patients, with half of them showing an increase in stromal TILs [17].

For the last 20 years, the question of whether primary debulking surgery or interval debulking surgery after neoadjuvant chemotherapy should be preferred in ovarian cancer surgery has been one of the most debated topics. Prospective studies have not shown the superiority of either of the two surgical options over the other [18, 19]. Although this approach may be associated with lower morbidity, there is a need for international consensus criteria for selecting patients and for parameters to predict which patients would benefit from neoadjuvant therapy.

Based on the available evidence, it appears that some factors can positively impact the survival of advanced ovarian cancer. These include achieving R0/1 cytoreduction after PDS or IDS, having a BRCA1/2 gene mutation, and having a complete or near-complete response [20].

BRCA1/2 status and the "chemotherapy response score" are both reliable markers of chemosensitivity. Patients who have a known germline BRCA mutation showed better outcomes with NAC than patients whose BRCA status is not known [21]. The CRS is a simple and consistent method for predicting the outcomes of patients with HGSC who have received neoadjuvant chemotherapy [8, 22]. They may be helpful in determining which patients should receive primary debulking surgery (PDS) or neoadjuvant chemotherapy followed by interval debulking surgery (NACT-IDS).

The researches indicate that breast cancer patients who demonstrate higher levels of PD-L1 expression experience a substantial improvement in their pCR response[23]. In addition, the presence of tumor-infiltrating lymphocytes (TILs) during breast cancer diagnosis is a prognostic marker for achieving pCR after treatment with neoadjuvant chemotherapy[24, 25]. Currently, there is a lack of research in the literature that evaluates the relationship in ovarian cancer. Our study revealed that there is a relationship between high levels of intratumoral PDL1 expression and CRS scores. Specifically, we observed that the incidence of CRS2 and CRS3 was higher among individuals with high PDL1 expression. The study highlighted the positive role of PD-L1 evaluation in assessing the probability of CRS.
Despite the limited number of participants, this study emphasizes the positive role of PD-L1 assessment in evaluating CSR. The PD-L1 status score seems to be becoming a valuable biomarker for predicting treatment outcomes based on our study. Patients who test negative for PD-L1 have a lower chance of achieving CRS and may need more intensive treatment for better outcomes. Therefore, if a patient is considered high-risk due to factors such as advanced age or pre-existing conditions, the presence of PD-L1 positivity could help the physician decide to use less aggressive treatment. It can serve as a predictive marker for response to standard neoadjuvant therapy. The varying scoring systems and detection methods for PD-L1 in different studies may have led to conflicting results regarding its expression. We suggest that a standardized pathology procedure should be created and implemented to address the limitation. Conducting further studies to establish a unified scoring system is highly recommended. PD-L1 and CD8+ TILs were studied only from the first tissue samples. We think that the effects of expression level variation in each patient on chemotherapy response can be better understood if samples from interval debulking surgery are also studied.

In conclusion, our findings suggest that levels of intratumoral PD-L1 expression in a diagnostic biopsy of ovarian cancer could serve as predictive biomarkers for the effectiveness of neoadjuvant chemotherapy prior to undergoing interval debulking surgery. We believe that, if supported by large-scale prospective studies, the PD-L1 expression level in the tumor before chemotherapy may be used as a test to predict the chemotherapy response.

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No competing interests reported.

Supplementarydata.docx

The predictive role of PD-L1 expression and CD8+ TIL levels in determining the neoadjuvant chemotherapy response in advanced ovarian cancer.

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Abstract

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INTRODUCTION

MATERIALS AND METHODS

RESULTS

DISCUSSION

References

Additional Declarations

Supplementary Files

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