Expression of immune response biomarkers (PD‑L1, p16, CD3+ and CD8+ TILs) in recurrent head and neck squamous cell carcinoma within previously irradiated areas
- Authors:
- Published online on: January 7, 2021 https://doi.org/10.3892/or.2021.7928
- Pages: 1273-1283
Abstract
Introduction
Recurrent head and neck squamous cell carcinoma (HNSCC) in previously irradiated areas and not accessible to local treatment usually have a poor prognosis, with a median overall survival of less than one year in the first-line setting (1–4).
Few therapeutic options are available, mostly as patients that have previously received irradiation are unsuitable candidates for salvage surgery, and often have unstable overall conditions (5). Today, salvage surgery remains the standard of care for selected operable and fit patients, but leads to a high rate of both local and regional failures (1,4).
The recent watershed of immunotherapy, particularly immune checkpoint inhibitors (ICIs), has provided renewed hope for recurrent and metastatic HNSCC; nivolumab treatment has resulted in a 30% reduction in risk of death (CheckMate 141 trial) (3,6) and pembrolizumab treatment in a 20% reduction (KEYNOTE-040 trial) (6,7). ICI use in patients with locoregional recurrence seems to be less satisfying than for metastases (3,7). Inhibition of the programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) pathway by these antibodies and the presence of CD8+ tumor-infiltrating lymphocytes (TILs) are of the greatest importance in terms of mounting an antitumor immune response (8).
Yet, the immune landscape of pretreated areas remains unclear, mainly because none of the randomized trials assessing the efficacy of ICIs stratified patients according to whether they had previously received radiation or not. Some investigators have already described the complexity of radio-induced alterations in growth factors and proinflammatory, profibrotic, and proangiogenic cytokines (9,10). It is well known that radiotherapy increases the mutational load and improves response to ICIs (11–13). Any changes in the frequency of CD3+ and CD8+ TILs or changes in the expression of PD-L1 by tumor and immune cells remain to be determined and if numbers or expression appear to be reduced, this could support the strategy for introducing an ICI earlier in future therapeutic approaches, as is being assessed in first-line recurrent or metastatic HNSCC and current studies KEYNOTE-048 (14), KEYNOTE-689 (Clinical Trial NCT03765918), PembroRad (Clinical Trial NCT02707588), KEYNOTE-412 (Clinical Trial NCT03040999), and REACH trial (Clinical Trial NCT02999087).
We focused on HNSCC locoregional recurrences as a recent study found a higher rate of hyperprogression following initiation of an ICI in patients with locoregional recurrence (with or without distant metastases) than in patients with only distant metastases (15), although this may be lower and more variable among solid tumors (16). We aimed to assess whether there is a difference in the expression of antitumor immune response biomarkers in the tumor microenvironment of de novo tumors and tumors in irradiated areas.
Materials and methods
Study design and patients
A total of 100 HNSCC tumor tissue specimens from patients who had undergone surgery from January 2010 to November 2017 were analyzed and divided into two cohorts: 50 de novo tumors and 50 tumors recurring within previously irradiated areas. The samples in the irradiated area came either from local recurrences at the initial tumor site, or from neck metastases or from second head and neck squamous cell carcinoma. Samples were included if they were paraffin-embedded surgical samples of invasive squamous cell carcinoma, from four locations (oral cavity, oropharynx, larynx, hypopharynx). Samples were excluded if they displayed other histology, carcinoma in situ, cancer at stage T1N0M0, tumors from the nasal or paranasal cavity or the nasopharynx, or if they were frozen tissue samples. All cases were recorded at the Lorraine Institute of Oncology and tissue specimens were obtained from the tumor bank of the Institute (tumor bank certification FR17/81842500; norm NF S96-900). According to French regulations, patients were informed of the research performed with tumor tissue specimens and did not object. We compared two parallel cohorts, de novo vs. pretreated (irradiated) area.
Histological assessment
Formalin-fixed and paraffin-embedded tumor tissue samples stained by hematoxylin, eosin, and saffron were reviewed by an experienced pathologist to check the quality and the representativity of the specimens selected for supplementary analysis with immunohistochemistry (IHC). IHC preparations were analyzed under microscopic examination. After hematoxylin counterstaining, tumor cells were differentiated from lymphocytes using morphologic criteria.
Immunohistochemical analysis
We used four monoclonal antibodies: Anti-PD-L1 ones, based on previous assessments of PD-L1 expression (17) (SP263, Ventana Medical Systems), anti-CD3 (SP7, Thermo Fisher Scientific, Inc.), anti-CD8 (C8/144B, Agilent Dako) and anti-p16 [anti-p16INK4a (E6H4), Ventana Medical Systems Inc.].
P16 status was assessed as a surrogate marker of human papillomavirus (HPV) association. Threshold positivity was at least 70% of tumor cells stained with at least moderate to strong and nuclear and cytoplasmic staining (18). The density of CD3+ and CD8+ TILs were measured quantitatively by counting each CD3+ or CD8+ cell in intratumoral and stromal compartments separately on photographs at magnification, ×20. Values were dichotomized (low/high) according to the median cell number calculated from all samples and considered high if >40 CD3+ cells and >30 CD8+ cells were observed in intratumoral regions and if >160 CD3+ cells and >90 CD8+ cells were observed in stromal regions. PD-L1 IHC expression, defined as membranous and cytoplasmic staining, was assessed on both tumor cells and immune cells. For tumor cells, threshold positivity was a tumor proportion score (TPS) ≥1%, as previously described (19,20). For immune cells, semi-quantitative assessment was carried out in both tumoral (categorized into three classes scored from 0 to 2) and stromal regions (categorized into six classes scored from 0 to 5). The expression of PD-L1 by immune cells was considered high with a score of 1–2 in intratumoral components and 2–5 in stromal components.
We also characterized the immune phenotype of samples of each cohort into four types as described by Teng et al based on TIL counts and expression of PD-L1 by tumor cells: Type I (adaptive immune resistance: PD-L1+/TILs high), type II (immunological ignorance: PD-L1-/TILs low), type III (intrinsic induction: PD-L1+/TILs low) and type IV (immune tolerance: PD-L1−/TILs high) (21). We considered TPS to be positive at ≥1% and CD8+ TIL numbers to be high when they were greater than or equal to the median cell number. Fig. 1 presents representative microphotographs of immunohistochemical staining.
Statistical analysis
Quantitative parameters were described as median and interquartile range or as mean and standard deviation according to the normality of the distribution assessed by the Shapiro-Wilk test; qualitative parameters as frequency and percentage. The two groups were compared by the Chi-square test or Fisher's exact test for qualitative parameters; for quantitative parameters, the Student's t-test was performed in case of normal distribution and the Mann-Whitney U test in the other cases. Each quantitative value of immune response biomarkers was dichotomized according to its median value.
In order to adjust the comparisons of immune response biomarkers on confounding factors, the propensity score was computed with the two groups as dependent parameters, and with patient and tumor characteristics with a P-value <0.2 for the comparisons of the two groups. The inverse probability of treatment weighting (IPTW) was computed (22) and immune response biomarkers were compared by weighting analyses. Progression-free survival (PFS) was defined as the time between surgery and relapse, progression, or death (whichever occurred first).
In each group, the prognostic factors of PFS were investigated according to the following process. First, bivariate analyses were performed with the Cox proportional hazard model. Parameters with a P-value <0.1 were introduced in a multivariate Cox proportional hazard model with backward selection. Results are presented as hazard ratio (HR) and its 95% confidence interval (CI). The statistical analyses were performed with SAS, version 9.4 (SAS Institute Inc.) and the significance level was set at 0.05.
Results
Patient and tumor characteristics
Table I presents the patient and tumor characteristics. Mean age was 64.2±8.3 years in the de novo cohort and 65.8±10.7 years in the irradiated area cohort (P=0.457). The two groups were well-balanced according to the following criteria: Sex (P=0.806), tumor location (P=0.743), and disease stage (P=0.873). Oropharyngeal tumors exhibited significantly greater p16 expression in the de novo cohort (n=7, 43.7%) than in the irradiated area cohort (n=2, 10.5%) (P=0.025). Tumors that had developed in irradiated areas were histologically less differentiated than the de novo tumors [n=32 (64.0%) vs. n=37 (74.0%) were well differentiated; P=0.051], and were more frequently stage pNx/N0/N1 [n=38 (76.0%) vs. n=26 (52.0%); P=0.012]. Resection margins were significantly more positive [n=23 (46.0%) vs. n=11 (22.0%); P=0.011]. Lymphovascular [n=21 (58.3%) vs. n=13 (30.2%); P=0.012] or perineural invasion [n=28 (73.7%) vs. n=23 (53.5%); P=0.060] were more frequently observed in the tumors that had developed in irradiated areas.
Treatment characteristics
Table II details the treatment characteristics. In the irradiated cohort, 22 (44.0%) patients had been treated with surgery and postoperative radiotherapy, 6 (12.0%) by surgery and postoperative chemoradiation, 10 (20.0%) by definitive chemoradiation, 5 (10.0%) by radiotherapy only, and 7 (14.0%) by induction chemotherapy and chemoradiation. Nineteen (44.2%) patients in the irradiated area cohort had received a mean irradiation dose at the site of tumor recurrence of ≥66 Gy (tumor and/or node). Table SI describes the treatments of the initial tumors of the irradiated area cohort.
Immune microenvironment
Table III details the immune microenvironment (CD3+ and CD8+ TILs, PD-L1) expression on tumor and immune cells) in the intratumoral and stromal regions.
 | Table III.Description of the expression of immune response biomarkers in irradiated area compared to de novo tumors. |
CD3+ TIL numbers
The median number of CD3+ TILs in the intratumoral regions was significantly lower in the irradiated area cohort [median, 20.5; interquartile range (9.0–70.0) vs. 58.0 (27.0–101.0); P=0.003].
A total of 34% of tumors in the irradiated area (n=17) showed a high CD3+ TIL count compared to 66% (n=33) in the de novo group (P=0.001). Similar results were found for CD3+ TIL count in the stromal regions (P=0.016). 36% (n=18) of irradiated tumors had a low number of CD3+ TILs in intratumoral and stromal regions compared to 14% (n=7) in the de novo group (P=0.001). Results were similar with the IPTW method.
CD8+ TIL numbers
CD8+ TIL counts did not differ between the two cohorts in either intratumoral or stromal regions. The median number was 21.5 [3.0–64.0] in the irradiated area cohort vs. 30.0 [13.0–87.0] in the de novo cohort in intratumoral compartments (P=0.273) and 71.0 {24.0–131.0} vs. 97.5 [48.0–158.0] in the stromal compartments (P=0.129).
Expression of PD-L1 by tumor and immune cells
The percentage of tumors with PD-L1+ tumor cells (TPS ≥1%) was significantly lower in the irradiated area cohort than the de novo cohort (56.0% vs. 86.0%, P<0.001) (Table III). The percentage of tumors with PD-L1+ immune cells was significantly lower in the intratumoral regions (48.0% vs. 72.0%, P=0.014) and also lower in the stromal regions (62.0% vs. 78.0%, P=0.081) in the irradiated area cohort compared to the de novo cohort. One-third of irradiated tumors had a negative TPS and a low expression of PD-L1 by immune cells (ICs) (Table III) compared to 10% in the de novo cohort (P=0.004). Results were similar using the IPTW method.
Immune phenotype
Fig. 2 presents the proportion of microenvironment phenotypes I to IV in each cohort. We observed type I phenotype, adaptive immune resistance, in 63% of tumors in the de novo cohort vs. 52% in the irradiated area cohort, whereas types II and IV were found more frequently in the irradiated area cohort (P=0.032 in bivariate analyses and P<0.001 after the IPTW method).
Median follow-up time was 18 months (interquartile range 10–27). The tumor microenvironment (CD3+ and CD8+ TILs, PD-L1+ tumor cells, and PD-L1+ immune cells) was not significantly associated with PFS in the de novo cohort (Table IV) or the irradiated area cohort (Table SII).
Discussion
The present study aimed to assess antitumor immune response biomarkers in head and neck squamous cell carcinoma (HNSCC) occurring in irradiated areas: Few data are currently available. We observed a significantly lower infiltration of CD3+ tumor-infiltrating lymphocytes (TILs) in tumors in irradiated areas compared to de novo tumors, in both intratumoral and stromal regions, a significantly lower expression of programmed death-ligand 1 (PD-L1) on tumor cells and immune cells, and no difference in CD8+ TIL infiltration, except for the high number of intratumoral CD8+ TILs, which was considered to be a statistical artifact.
As there are no randomized clinical trials stratified according to whether patients had previously received radiation or not, we had no comparative data; lower PD-L1 expression by tumor and immune cells or lower numbers of TILs, whether in intratumoral or stromal compartments, might have been expected, as immune checkpoint inhibitors (ICIs) seem to be less effective for locoregional relapses than for metastatic lesions (3). Our results confirm the hypothesis that antitumor treatments modify the microenvironment of recurrent tumors, especially for radiotherapy. This is why trials are being conducted with concomitant strategies such as PembroRad (Clinical Trial NCT02707588), KEYNOTE-412 (Clinical Trial NCT03040999) and REACH trial (Clinical Trial NCT02999087).
In the irradiated area cohort, we observed a lower CD3+ TIL count, which may suggest that pretreated tumors belong to immunologically unresponsive group of tumors, as Yuan et al described (23). However, there was a persistent infiltration of CD8+ TILs in tumors from irradiated areas. CD8+ TILs are cytotoxic T lymphocytes and therefore play a major role in antigen-specific antitumor immune responses (24). Studies of several malignant tumors have revealed that the frequency of CD8+ and CD3+ TILs has a prognostic value (25–28). Although we observed slightly lower densities of CD8+ TILs in the irradiated area cohort than in the de novo cohort, previous radiation therapy or chemoradiation did not significantly affect their presence.
This therefore highlights that irradiated tissues retain the ability for antitumor action, as the main driver leading to immune response is the preexistence of antitumor cytotoxic T cells that were specifically hampered by immune checkpoints (8). It may corroborate previous observations that radiotherapy has the capacity to recruit CD8+ TILs that are specific to tumor antigens and to increase the expression of PD-L1 (29).
Moreover, it constitutes a strong rationale for the use of ICI treatment for tumors occurring in previously treated areas, in order to activate cytotoxic antitumor immune responses. This is being assessed in the ADJORL1 trial (Clinical Trial NCT03406247), which is investigating the use of immunotherapy after salvage surgery for previously treated tumors.
CD3+ TILs are important, as CD3 is a T cell co-receptor that aids activation of both cytotoxic cells and T helper cells. The persistent rate of cytotoxic CD8+ TILs and the reduction in CD3+ TILs could reflect a decrease in other classes of T cells, such as helper T cells or regulatory T cells.
Our results do not explain why locoregional recurrences can be the center of hyperprogression when using ICIs and may suggest that other mechanisms are likely to be involved. To date, we do not yet understand why the rate of hyperprogression, which can range from 9 to 29%, is greater in locoregional recurrences compared to distant metastases; prospective trials should investigate this further (15,16,30).
Significantly fewer tumors in the irradiated area cohort expressed PD-L1 on tumor cells than in the de novo cohort, but more than half (56%) were positive according to our cut-off of ≥1%. This reduction compared to de novo tumors may provide first indicators of why these tumors are less responsive to immunotherapy and lend weight to the argument of introducing ICIs earlier in therapeutic strategies for HNSCC, associated or not with cytotoxic agents or radiation. This was the rationale behind the KEYNOTE-048 phase III randomized trial, which showed a significantly longer overall survival in the frontline setting with anti-PD-1 pembrolizumab monotherapy vs. the EXTREME regimen [12.3 months vs. 10.3 months for the PD-L1 combined positive score (CPS) ≥1 population and 14.9 months vs. 10.7 months for the PD-L1 CPS ≥20 population] (14). The pembrolizumab with chemotherapy arm also showed a significantly longer overall survival in the frontline setting vs. the EXTREME regimen (13.6 months vs. 10.4 months for the PD-L1 CPS ≥1 population and 14.7 months vs. 11.0 months for the PD-L1 CPS ≥20 population) (14).
The PembroRad phase II randomized trial (Clinical Trial NCT02707588) is evaluating pembrolizumab combined with radiotherapy vs. cetuximab combined with radiotherapy in locally advanced HNSCC (LA HNSCC), and preliminary data seem to indicate a good tolerance (31). Other trials are assessing combination strategies with ICIs, such as the REACH trial, assessing the anti-PD-L1 antibody avelumab combined with cetuximab and radiotherapy (Clinical Trial NCT02999087), the KEYNOTE-412 trial, assessing pembrolizumab combined with chemoradiation (Clinical Trial NCT03040999) in LA HNSCC, or the JAVELIN trial, assessing avelumab in combination with chemoradiation in LA HNSCC (Clinical Trial NCT02952586).
Interestingly, our study indicates that patients with tumors in previously irradiated areas could be the best candidates to receive the addition of anti-CTLA4 to anti-PD-1/PD-L1 agents, as we found a significantly lower expression of PD-L1 on tumor cells in these tumors. Indeed, anti-CTLA4 agents seem to recruit CD8+ TILs and their combination with anti-PD-1/anti-PD-L1 agents has a strong rationale for the induction of an antitumor immune response, especially when expression of PD-L1 is low. Trials assessing the combination of anti-CTLA4 and anti-PD-1/PD-L1 agents are ongoing, including the KESTREL phase III randomized trial (Clinical Trial NCT02551159) and the CheckMate 651 phase III randomized trial (Clinical Trial NCT02741570). However, CheckMate 714 phase II trial results were negative, suggesting that a combination of chemotherapy and immunotherapy could be of more interest than combining immunotherapies (Clinical Trial NCT02823574).
Various tumor proportion score (TPS) thresholds are used in different studies of HNSCC, with the cut-off ranging from 1 to 50%, illustrating that debate exists around choosing a threshold (3,7,28,32). We analyzed data from both intratumoral and stromal regions; there is currently no clear consensus on whether PD-L1 expression on all cells or specific cell populations should be analyzed, and which emergent scores should be used (6). CPS is one of these emergent scores, which takes into account the ratio of PD-L1 expressing cells to the total number of tumor cells and was able to predict response to pembrolizumab (7,14). An elevated pretreatment neutrophil-to-lymphocyte ratio can also predict poor prognosis with local invasion and distant metastases (33).
Immune phenotype
The predominant tumor microenvironment type in the irradiated area cohort was adaptive immune resistance (type I). Yang et al noted that HNSCC had typically diverse profiles of TILs, dividing tumors into two main categories: Inflamed or non-inflamed (24) Lei et al suggested that an immunoscore based on TIL phenotype may be helpful in better classifying patients (34). This study shows that tumors in irradiated areas can be still inflamed and links to ideas from Teng et al, who suggested that anti-PD-1/PD-L1 agents may be most effective in tumors with type I/inflamed microenvironments, because of preexisting intratumoral T cells (21). The persistent infiltration of CD8+ TILs shown in this study is encouraging for this entity of tumors occurring in patients who have previously received radiation, since CD8+ TILs have recently been presented as a promising favorable prognostic biomarker in HNSCC after adjuvant chemoradiation (28). However, given the known poor prognosis of patients with these tumors, CD8+ TILs may be dysfunctional T cells, as Psyrri et al suggested when studying the mechanisms of resistance to nivolumab (35).
Prognostic factors in the de novo cohort were advanced stage and site of disease; our results are consistent with previous findings that tumors in the hypopharynx have a poor prognosis (36,37). Expression of PD-L1 on immune cells tended to be a PFS prognostic factor. In the irradiated area cohort, no relevant prognostic factor was highlighted, which could be explained by the initial poor prognosis. Indeed, we found the same tumor characteristics that have previously been shown to confer a poor prognosis for patients with locoregional relapses: Poor differentiation, high pN stage, positive resection margins, and lymphovascular or perineural invasion (Table I).
Yang et al performed a meta-analysis of studies that assessed the prognostic role of PD-L1 expression in HNSCC (24). They concluded that PD-L1 could not be recommended as a prognostic factor in HNSCC, nor could it be used to stratify the risk in HPV-related HNSCC.
While PD-L1 has mainly been described as a prognostic factor when expressed on tumor cells (PD-L1+ tumor cells), the importance of immune cells (PD-L1+ immune cells) is beginning to be revealed. Indeed, Kim et al depicted PD-L1+ immune cells as a favorable prognostic factor in HNSCC with a positivity cut-off of 5% (38). The two-year follow-up data from CheckMate 141 described an OS benefit with nivolumab irrespective of PD-L1 expression (39), suggesting that PD-L1-negative patients may benefit from ICI treatment because of PD-L1 expression by stromal cells. Kim et al also found that PD-L1 expressed by immune cells was a favorable prognostic factor in HNSCC (38) and some trials have started to use PD-L1 expression as a stratification factor, such as the IMpassion130 trial in triple-negative breast cancer (40).
The limitations of this study include the bias typical of retrospective studies and the fact that patients had not received ICI treatment, as clinical trials using immunotherapy were ongoing.
In conclusion, our results show the persistence of cytotoxic cells but lower expression of PD-L1 and fewer CD3+ TILs in tumors in irradiated areas. This study provides first potential explanations of the fact that these lesions are less responsive to immunotherapy, although they may still retain antitumor capacities. The assessment of immune response biomarkers in patients treated with immunotherapy in randomized trials is required to decipher the molecular mechanisms involved in acquired resistance to treatments.
Supplementary Material
Supporting Data
Acknowledgements
We would like to thank the english language editing service.
Funding
Funding for this research project was provided by the Lorraine Institute of Oncology.
Availability of data and materials
All data generated or analyzed during this study are included in this published article.
Authors' contributions
All authors contributed equally to this research study. CP, JS, XSG and LG conceived and designed the experiments. CP, JT, JCF and GD made substantial contributions to acquisition of the data. XSG performed the histological examination. CP, JS, XSG and LG analyzed and interpreted the patient data. CB was involved in revising the manuscript critically. All authors were involved in the writing of the manuscript and approved the final manuscript.
Ethics approval and consent to participate
All patients were managed in the Lorraine Institute of Oncology according to the standards of good clinical practice. This retrospective study was approved by the local institutional review board and has been declared to Commission for information technology and civil liberties (‘CNIL’), registered as a standard declaration by CNIL correspondent of the Institute. All patients were informed of the research performed with tumor tissue specimens and gave their consent. Ethical approval was not necessary for this retrospective study.
Patient consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
Glossary
Abbreviations
Abbreviations:
|
HNSCC |
head and neck squamous cell carcinoma |
|
HPV |
human papillomavirus |
|
ICIs |
immune checkpoint inhibitors |
|
PD-L1 |
programmed death-ligand 1 |
|
TILs |
tumor-infiltrating lymphocytes |
|
TPS |
tumor proportion score |
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