Survival benefit for HPV+ OPSCC patients with dominant serum IgA over IgG antibodies against HPV16 L1

doi:10.21203/rs.3.rs-3091545/v1

Background

Although the therapy response of HPV-positive oropharyngeal carcinomas (OPSCC) is known to be significantly better compared to HPV-negative tumors, about 25% of them will have a recurrence within the first 5 years after therapy. Therefore, it is of great scientific interest to find relevant biomarkers to identify subgroups with a poorer prognosis. In this prospective observational study, we examine for the first time the behavior of HPV-L1 antibody subclasses IgA, IgG, and IgM in HPV-positive OPSCC patients under therapy.

Material and Methods

The study cohort included patients with HPV-positive OPSCCs from the Department of Otorhinolaryngology, Head and Neck Surgery, Medical University of Graz. Serum samples were collected before and during tumor-specific therapy and follow-up. They were analyzed for the presence of HPV-L1 antibody (AB) subclasses IgA, IgM, and IgG using an HPV-L1-specific immuno-assay. In addition, a PCR-based HPV-DNA detection and subtyping from the tumor tissue was performed. Statistical analysis included Chi²- and Kruskal-Wallis-H-Test for significance testing. Correlation between two ordinal sizes has been tested using Spearmen-Rho.

Results

Altogether, 34 patients with a mean age of 63.5 years and a mean follow-up of 55 months were included. The most common L1-AB-subclass pattern was characterized by IgG > > IgA > IgM (13 cases) without significant fluctuation. The second most common pattern was IgG > IgA > IgM (6 cases). In 5 cases an antibody pattern of IgA > IgG > IgM while in 4 cases IgG = IgA > IgM was seen. Three out of 4 recurrences had previously shown an increase in IgG antibodies. Patients with excessive IgG levels tended to have higher tumor stages. IgA dominance at diagnosis was associated with better disease-free survival.

Conclusions

In this prospective longitudinal observational study, we show for the first time the behavior of HPV-L1 antibody subclasses IgA, IgG, and IGM in HPV-positive OPSCC patients under therapy. IgA dominance at diagnosis was associated with better disease-free survival, whereas a higher IgG/IgA ratio correlated with higher tumor stages. In three recurrent tumors, an increase in the IgG AB level could be shown beforehand. HPV-L1 AB-subclass detection might be of use for future risk stratification in HPV-pos. OPSCC patients.

HPV-positive oropharyngeal carcinoma

antibodies

antibody subclasses

biomarker

Although vaccination coverage against HPV-associated cancers is increasing, incidence of these entities have been shown to be on the rise(1). While cases of cervical cancer are declining in countries with structured immunization programs, increasing incidence of HPV-associated oropharyngeal squamous cell carcinoma (OPSCC) have already overtaken those of cervical cancer in certain countries(2). OPSCC is even estimated to become one of the most common cancers in middle-aged men in the United States by 2045(3). Nonetheless, it was shown that HPV-driven OPSCCs are associated with a better prognosis and a lower recurrence rate compared to their HPV-negative counterparts(4, 5). These findings were incorporated into the 8th edition of the UICC/AJCC classification, which distinguishes between HPV-positive and negative OPSCCs by the use of p16 immunohistochemistry (IHC) (6). HPV-positive OPSCC is considered more sensitive to chemotherapy, radiation treatment and combined treatment protocols compared to its HPV-negative counterpart, making p16 IHC the most important prognostic marker in this tumor entity(7, 8). A recent study by Mehanna et al. showed that there is often a discrepancy between p16 IHC detection and HPV DNA or RNA status, reflected in a poorer prognosis in the case of p16 IHC+/HPV- patients(9). The existence of a subgroup with poorer prognosis within prognostically favored group of HPV-positive OPSCCs might explain poorer outcomes in dose de-escalation prospective studies (10–13). Another hypothesis assumes that certain genetic subtypes of HPV-positive OPSCCs result in different therapy responses(14). Reliable biomarkers for risk stratification of these patients to better adapt therapy regimens and evaluate therapy success are urgently needed. Since it is known that immune responses are important not only concerning the development of tumors but also for prognostic information, an important question is what role the immune system plays in the success of therapy and to what extent the immune response can be mapped(15). In a previous study, we prospectively examined OPSCC patients with a subtype-specific competitive serological assay based on an HPV16-L1-specific monoclonal antibody (AB) before and after therapy, showing that antibody titers in most cases reflect the course of disease (16, 17). We have also shown in individual cases that an increase in the HPV-L1 antibody titer could indicate a possible recurrence of the disease(16, 17).

In this study, we aimed to investigate the immune response at the level of HPV-L1 antibody subclasses IgA, IgM, and IgG in the context of tumor-specific therapy and follow-up in a cohort of HPV-associated OPSCC patients.

In this prospective observational study, serum samples from patients with histologically confirmed OPSCC were collected at the Department of Otorhinolaryngology, Head and Neck Surgery of the Medical University of Graz before and after tumor-specific therapy and in the post-therapeutic follow-up. Only patients with p16-positive tumors (p16 Histology KIT, Ventana Roche Diagnostics, Switzerland) were included. Furthermore, PCR-based HPV DNA detection (HPV 3.5 LCD Array KIT, Chipron®, Germany) was performed. Patients with recurrent or secondary tumors in the head and neck area, patients in a poor general condition not suitable for any curative tumor-specific therapy, and patients with severe cognitive impairment were excluded from this study. Study participants were asked about their HPV vaccination status in the context of study enrollment and their medical history was screened for other HPV-induced diseases, like anogenital carcinoma.

Clinical data was recorded for all patients. As part of the oncological follow-up examination, in accordance with national guidelines, CT or MRI of the tumor region was carried out once a year, and an ENT examination including endoscopy and sonography of the soft tissue of the neck was carried out at scheduled visits every 3 to 6 months.

Serum samples were collected at the time of diagnosis, under therapy and during follow-up visits 3 and 6 months after completion of therapy. Serum samples were analyzed for the presence of the HPV-L1-AB subclasses IgA, IgM, and IgG using a commercially available HPV16- and HPV33-specific immuno-assay (Abcerion Diagnostics GmbH, Germany). In short, serum samples were incubated with HPV L1-specific antigen-captured microtiter plates. After a washing step antibody subclass-specific detection was carried out using horseradish peroxidase (HRP) conjugated anti-IgA, IgM, and IgG antisera. Ready to use tetramethylbenzidine (TMB) was used for color development, and sulfuric acid as a stopping solution. Test results were documented by using a microtiter plate reader, according to the manufacturer’s instructions.

In statistical analysis Kolmogorow-Smirnow-Tests and Shapiro-Wilk-Tests have been used to test for normality. Frequencies in nonparametric data are shown with median and range. Chi2-test and Kruskal-Wallis-H-Test have been used for significance testing in two independent, qualitative samples, and > 2 independent nonparametric samples. Correlation between two ordinal sizes has been tested using Spearmen-Rho.

Each patient signed an informed consent form, and the study was approved by the local ethics committee of the Medical University of Graz.

Study cohort

We identified 34 cases, 27 male and 7 female, diagnosed with HPV-positive OPSCC between 2016 to 2021. The median age at diagnosis was 63.50 years (range 46–89). Tobacco consumption of ≥ 20 pack years (PY) was reported in eleven cases (31.4%), and five patients (14.7%) reported regular alcohol consumption. Only 4 cases (11.8%) presented with an ECOG score of 1, the remaining cases presented with a score of 0. The tumor was localized in the palatal tonsils (79%) and the base of the tongue (BOT) (15%). Two cases have been diagnosed as CUP. Most cases (27/34, 79.4%) presented with early-stage disease (AJCC staging I and II). Six cases (17.6%) presented with stage III disease and one case (2.9%) with stage IV disease. All cases stained positive for p16. The most frequently identified HPV genotype was HPV16 (88%) followed by HPV33 (6%). PCR for HPV was negative in 2 cases. The median follow-up time was 55 months. See Table 1 for an overview of patient characteristics.

Table 1: Clinical characteristics of study population

			Number of patients
Gender		Male	27
Gender		Female	7
Age^a
	Median		63,50
	Range		46 - 89
Smoker^b		no	23
Smoker^b		yes	11
Alcohol^c		no	29
Alcohol^c		yes	5
ECOG^d		0	30
		1	4
		2	0
		3	0
		4	0
		5	0
AJCC-staging^e		I	13
		II	14
		III	6
		IV	1
HPV-DNA		HPV 16	30
		HPV 33	2
		negative	2
p16-IHC		positive	34
p16-IHC		negative	0
Localisation		Tonsillar complex	27
		Base of the tongue	5
		CUP	2
a. Age at Diagnosis, b. Yes = ≥20 PY, No = <20 PY, c. regular alcohol consumption, d. ECOG at diagnosis, e. AJCC staging for p16 pos. cases

Recurrence was reported in 4 cases: following surgery (1), surgery + radiochemotherapy (RCT) (1), or radioimmunotherapy (RIT) (2). The time to relapse was between 10 and 65 months. The primary location has been the tonsils (3), or the BOT (1). Patients with relapse were male, aged between 57 and 83. Only one of the relapsed patients has had a positive smoking history and reported regular alcohol consumption at diagnosis. HPV16-DNA has been identified in all cases of recurrence. Relapse was not associated with advanced tumor stage. Three out of four patients received second-line therapy (SLT). SLT included immunotherapy (2) or radiotherapy (1). Two out of three patients treated with RTX or IT developed progressive disease following second-line therapy. See Table 2for an overview of treatment regimes and therapy success.

Table 2

Overview of treatment regimes and therapy success
First-line therapy		Best response to first-line therapy	Relapse	Second-line therapy		Best response to second-line therapy
	Number of patients	CR^f			Number of patients		Number of patients
RTX^a	2	2	0
RIT^b	3	3	2	IT^d	1	PD^g	1
RIT^b	3	3	2	NT^e	1	LOFU^h	1
RCT^c	9	9	0
RCT + RIT	1	1	0
Surgery	3	3	1	RTX	1	PD	1
Surgery + RCT	10	9	1	IT	1	SDⁱ	1
Surgery + RTX	6	6	0
a. Radiotherapy, b. Radioimmunotherapy, c. Radiochemotherapy, d. Immunotherapy, e. No treatment, f. Complete remission, g. Progressive disease, h. Lost to follow-up, i. Stable disease

Evaluation of HPV-L1 antibody subclasses:

In our cohort, 28 patients had adequate samples for evaluation of IgG, IgA, and IgM levels over time. The most prevalent L1-antibody pattern (found in 13 cases) is characterized by IgG > > IgA > IgM. The second most prevalent pattern is IgG > IgA > IgM (detected in 6 cases). Five and four cases show IgA > IgG > IgM and IgG ≈ IgA > IgM, respectively. (Fig. 1)

There were four patients (Cases 3, 10, 12, and 10) with recurrent disease following first-line therapy (Fig. 2).

Relapse was associated with an increase of HPVL1-IgG in cases 3, 10, and 12. In Cases 10 and 12, L1-IgG increased 4, and 2 months prior to relapse, respectively. Case 3 did present a similar, but not equal pattern, due to a delay of 7 months between relapse and consecutive sampling. Relapse was not associated with an increase of IgG in Case 20. At diagnosis we found IgA over IgG levels in case 12, switching to IgG over IgA several months before relapse was diagnosed. Cases 12 and 20 both had higher IgA levels compared to Cases 3 and 10. We were not able to identify significant differences regarding IgM levels in Cases 10, 12, and 20. IgM peaked approx. 2 months following surgery in case 3 and consecutively declined over the following 4 years. (Fig. 2) Although not statistically significant (Chi² p = 0.261), we found that the more dominant the IgG level is, the more prevalent are higher AJCC-stages. (Fig. 3)

IgG/IgA-Ratio at diagnosis did not significantly differ between AJCC-subgroups (Kruskal-Wallis-H-Test p = 0.326). We also did not observe a significant correlation between higher AJCC-stages and IgG/IgA-ratio at diagnosis using the Spearmen-Rho Test (p = 0.149).

We conducted a study to analyze the distribution of post-treatment L1-AB subclasses in HPV-positive OPSCC over time. To our knowledge this is the first study, in which AB-kinetics of L1-IgG, -IgA, and -IgM are investigated over time.

In HPV-positive OPSCCs the tonsillar complex and the BOT are the most frequently reported locations (96%)(18). Our study cohort included carcinomas located only in these two areas. This is of importance, as a retrospective analysis in 23 297 patients by the US National Cancer Database found that HPV-positive OPSCCs located outside the tonsillar areas are associated with an inferior overall survival compared to carcinomas located in the tonsils (HR: 0.76, 95% CI: 0.67–0.86, P < .0001)(19). In our patient cohort HPV 16 and 33 have been identified in ~ 88% and ~ 7%, respectively. These findings are in concordance with previously published data by Amanda et al., who found that high-risk HPV16 is by far the most prevalent HPV subtype (18). In concordance with data published by Khalid et al., most of our patients presented with small tumors (T1, T2; ~18%, ~ 53%) and nodal metastases (N1, N2; ~24%, ~ 62%) at diagnosis(20).

Although HPV-positive OPSCC is associated with a favorable prognosis, up to 25% develop relapsing disease 2–5 years after first-line treatment(21). Hence robust and easy-to-use clinical monitoring is needed to effectively evaluate post-treatment disease status. In the past few years different serological tests have been studied in HPV-positive OPSCC. Antibody-based serological tests revealed that E6 and E7 oncoproteins of high-risk HPVs strongly correlate to HPV-driven malignancies, whereas L1-antibodies are regarded as cumulative-exposure markers(22, 23). Oton-Gonzales et al. used a commercial kit (HPV16 L1, Cusabio, Houston, TX, USA) to investigate serological L1-IgG kinetics in 20 HPV-positive HNSCC cases(22). They found that L1-IgG antibody levels did not significantly fluctuate during a follow-up period of 24 months (p > 0.05)(22). Piontek and co-workers conducted a study in 184 HPV16-driven invasive cervical cancer patients to characterize post-treatment AB-dynamics using multiplex HPV serological testing (GST-derived antigens)(23). They showed that L1 antibody levels are stable over time whereas E6 and E7 AB levels decreased after cervical cancer treatment(23). Both studies confirm the hypothesis that L1 IgG-ABs remain stable over time. In contrast to available data, findings of our previously published paper suggest that HPV16-L1 DRH1 epitope-specific antibodies are linked to HPV16-induced tumor recurrence(16). In the current study four different patterns of antibody-dynamics have been identified in the following frequency: 1. IgG > > IgA > IgM, 2. IgG > IgA > IgM, 3. IgA > IgG > IgM, and 4. IgG ≈ IgA > IgM. Although not statistically significant (p = 0.326), higher IgG/IgA-Ratios at diagnosis gravitated towards higher AJCC-stages. These findings indicate that the dominance of IgG at the time of diagnosis might play an important role in further risk-stratification of HPV-positive OPSCCs. Relapse was in 3 out of 4 cases associated with an increase of HPVL1-IgG beforehand, which, on the other hand, would support the conclusion of our previous study that HPV-L1 antibody detection might be used as a post-treatment biomarker.

Although analyses of the entire cohort did not show statistically significant AB-fluctuation over time (mainly due to the small sample size), individual antibody profiles revealed some interesting abnormalities. (Fig. 4)

Serum IgA dominance at diagnosis has been observed in 50% (2/4) cases primary located at the BOT. The remaining two cases presented with IgG dominance but subsequently switched to IgA dominance over time. IgA dominance at diagnosis in cases primary located at the tonsillar complex, has been found in 16,6% (3/18) cases. In one case IgA and IgG antibodies reached an equal level over time. IgA dominance at diagnosis has been associated with a superior disease-free survival. Only one out of seven cases developed relapse, associated with an IgA to IgG switch several months prior to clinical diagnosis of tumor recurrence. We observed an IgA to IgG switch in one additional case, but so far without any hint of disease recurrence. IgG dominance at the time of tumor recurrence has been found in all four clinically confirmed recurrences. So far there is no reasonable explanation for the association between superior clinical outcome and serum IgA dominance over time. Literature supports the assumption that IgA is the predominant AB-subclass found in saliva, and IgG in serum(24). IgM to IgA AB-class switch in naive B-cells seems to be predominantly controlled by TGF-β(25). HPV E6/E7 oncoproteins can upregulate TGF-β promotor activity resulting in TGF-β overexpression, which stimulates survival and proliferation of cervical cancer cell lines. Interestingly, TGF-β overexpression has also been described in OPSCC(26). It is unclear whether OPSCC-cells themselves or cells of the tumor microenvironment are responsible for the expression of different amounts of TGF-β which may explain IgA or IgG dominance. Von Witzleben and colleagues found that HPV E2 and E7 related IgA antibodies have not been associated with a superior overall survival in HPV-positive OPSCC patients, which may be indicative that the observed effect could rather be related to the HPV late proteins. A reason for this difference could be the high molecular weight of L1 based virus like particles that in contrast to the very small early proteins are able to bind to toll like receptors (TLR4) of the innate immune system, possibly thereby changing the cytokine network of the tumor microenvironment which in turn may influence the adaptive immune response as well(27).

In conclusion, our findings indicate that HPV-L1 AB-subclass analyses may add additional value to risk-stratification at diagnosis and for monitoring potential relapsing disease in HPV-positive OPSCC. Nonetheless, further investigations are needed to better characterize immunologic mechanisms, which may explain superior clinical outcomes in IgA dominant HPV-positive OPSCC- cases.

AB: Antibody

ADCC: Antibody-dependent cell-mediated cytotoxicity

BOT: Base of tongue

HPV: Human papilloma virus

HRP: Horseradish peroxidase

IT: Immunotherapy

OPSCC: Oropharyngeal squamous cell carcinoma

PY: Pack years

RTX: Radiotherapy

RIT: Radioimmunotherapy

RCT: Radiochemotherapy

SLT: Second-line therapy

TLR: Toll like receptors

TMB: Tetramethylbenzidine

Ethics approval and consent to participate

The study was approved by the local ethics committee of the Medical University of Graz (EK-Nr.: 28-378 ex 15/16) and carried out according to the Declaration of Helsinki on biomedical research on humans. Patient informed consent forms were obtained from all included patients.

Consent for publication

Not applicable.

Availability of data and materials

All data generated or analyzed during this study are included in this published article.

Competing interests

The authors declare that they have no competing interests.

Funding

No funding was received for this work.

Authors’ contributions

TW: conception and design, collection of data, data interpretation, manuscript writing

JZ: data interpretation, manuscript writing, statistics

LB: collection of data, manuscript review/editing

DT: manuscript review/editing

Acknowledgements:

Not applicable.

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No competing interests reported.

Survival benefit for HPV+ OPSCC patients with dominant serum IgA over IgG antibodies against HPV16 L1

Status:

Version 1

Abstract

Background

Material and Methods

Results

Conclusions

Figures

Introduction

Materials and Methods

Results

Study cohort

Evaluation of HPV-L1 antibody subclasses:

Discussion

Abbreviations

Declarations

References

Additional Declarations

Status:

Version 1