Chordoma cancer stem cell subpopulation characterization may guide targeted immunotherapy approaches to reduce disease recurrence.

Introduction: Cancer stem cells (CSCs), a group of tumor-initiating and tumor-maintaining cells, may be major players in the treatment resistance and recurrence distinctive of chordoma. Characterizing CSCs is crucial to better targeting this subpopulation. Methods: Using flow cytometry, six chordoma cell lines were evaluated for CSC composition. In vitro, cell lines were stained for B7H6, HER2, MICA-B, ULBP1, EGFR, and PD-L1 surface markers. Eighteen resected chordomas were stained using a multispectral immunofluorescence (mIF) antibody panel to identify CSCs in vivo. HALO software was used for quantitative CSC density and spatial analysis. Results: In vitro, chordoma CSCs express more B7H6, MICA-B, and ULBP1, assessed by percent positivity and mean fluorescence intensity (MFI), as compared to non-CSCs in all cell lines. PD- L1 percent positivity is increased by >20% in CSCs compared to non-CSCs in all cell lines except CH22. In vivo, CSCs comprise 1.39% of chordoma cells and most are PD-L1+ (75.18%). A spatial analysis suggests that chordoma CSCs cluster at an average distance of 71.51 mm (SD 73.40 mm) from stroma. Discussion: To our knowledge, this study is the first to identify individual chordoma CSCs and describe their surface phenotypes using in vitro and in vivo methods. PD-L1 is overexpressed on CSCs in chordoma human cell lines and operative tumor samples. Similarly, potential immunotherapeutic targets on CSCs, including B7H6, MICA-B, ULBP1, EGFR, and HER2 are overexpressed across cell lines. Targeting these markers may have a preferential role in combating CSCs, an aggressive subpopulation likely consequential to chordoma's high recurrence rate.

Targeting sinonasal undifferentiated carcinoma with a combinatory immunotherapy approach.

PURPOSE: Sinonasal undifferentiated carcinoma (SNUC) is a rare, aggressive malignancy of the sinonasal cavity with poor prognosis and limited treatment options. To investigate the potential for SNUC sensitivity to combinatory immunotherapy, we performed in vitro studies with SNUC cell lines and used multi-spectral immunofluorescence to characterize the in vivo patient SNUC tumor immune microenvironment (TIME). EXPERIMENTAL DESIGN: Human-derived SNUC cell lines were used for in vitro studies of tumor cell susceptibility to natural killer (NK) cell-based immunotherapeutic strategies. Tumor samples from 14 treatment naïve SNUC patients were examined via multi-spectral immunofluorescence and clinical correlations assessed. RESULTS: Anti-PD-L1 blockade enhanced NK cell lysis of SNUC cell lines ∼5.4 fold (P ≤ 0.0001). This effect was blocked by a CD16 neutralizing antibody demonstrating activity through an antibody-dependent cellular cytotoxicity (ADCC) mediated pathway. ADCC-dependent lysis of SNUC cells was further enhanced by upregulation of PD-L1 on tumor cells by exogenous interferon-gamma (IFN-γ) administration or interleukin-15 (IL-15) stimulated IFN-γ release from NK cells. Combination treatment with anti-PD-L1 blockade and IL-15 superagonism enhanced NK-cell killing of SNUC cells 9.6-fold (P ≤ 0.0001). Untreated SNUC patient tumor samples were found to have an NK cell infiltrate and PD-L1+ tumor cells at a median of 5.4 cells per mm2. A striking 55.7-fold increase in CKlow tumor cell/NK cell interactions was observed in patients without disease recurrence after treatment (P = 0.022). Patients with higher CD3+CD8+ in the stroma had a significantly improved 5-year overall survival (P = 0.0029) and a significant increase in CKlow tumor cell/CD8+ cytotoxic T cell interactions was noted in long-term survivors (P = 0.0225). CONCLUSION: These data provide the pre-clinical rationale for ongoing investigation into combinatory immunotherapy approaches for SNUC.

Recurrent Wnt Pathway and ARID1A Alterations in Sinonasal Olfactory Carcinoma.

Sinonasal tumors with neuroepithelial differentiation, defined by neuroectodermal elements reminiscent of olfactory neuroblastoma (ONB) and epithelial features such as keratin expression or gland formation, are a diagnostically challenging group that has never been formally included in sinonasal tumor classifications. Recently, we documented that most of these neuroepithelial neoplasms have distinctive histologic and immunohistochemical findings and proposed the term "olfactory carcinoma" to describe these tumors. However, the molecular characteristics of olfactory carcinoma have not yet been evaluated. In this study, we performed targeted molecular profiling of 23 sinonasal olfactory carcinomas to further clarify their pathogenesis and classification. All tumors included in this study were composed of high-grade neuroectodermal cells that were positive for pankeratin and at least 1 specific neuroendocrine marker. A significant subset of cases also displayed rosettes and neurofibrillary matrix, intermixed glands with variable cilia, peripheral p63/p40 expression, and S100 protein-positive sustentacular cells. Recurrent oncogenic molecular alterations were identified in 20 tumors, including Wnt pathway alterations affecting CTNNB1 (n = 8) and PPP2R1A (n = 2), ARID1A inactivation (n = 5), RUNX1 mutations (n = 3), and IDH2 hotspot mutations (n = 2). Overall, these findings do demonstrate the presence of recurrent molecular alterations in olfactory carcinoma, although this group of tumors does not appear to be defined by any single mutation. Minimal overlap with alterations previously reported in ONB also adds to histologic and immunohistochemical separation between ONB and olfactory carcinoma. Conversely, these molecular findings enhance the overlap between olfactory carcinoma and sinonasal neuroendocrine carcinomas. A small subset of neuroepithelial tumors might better fit into the superseding molecular category of IDH2-mutant sinonasal carcinoma. At this point, sinonasal neuroendocrine and neuroepithelial tumors may best be regarded as a histologic and molecular spectrum that includes core groups of ONB, olfactory carcinoma, neuroendocrine carcinoma, and IDH2-mutant sinonasal carcinoma.

Increasing radiation therapy and lower survival for human papillomavirus-related oropharynx cancer associated with a shift to community cancer center care.

BACKGROUND: Studies have shown lower overall survival for patients with head and neck cancer treated at low-volume or community cancer centers. As the incidence of human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma steadily rises in the United States, we hypothesized that a greater proportion of patients with HPV-related oropharyngeal squamous cell carcinoma is being treated at community cancer centers, with a shift toward primary nonsurgical treatment. METHODS: This cohort study included patients from the US National Cancer Database who received a diagnosis of HPV-related oropharyngeal squamous cell carcinoma from 2010 to 2019 and underwent treatment at a community cancer center or academic cancer center. The proportion of patients with HPV-related oropharyngeal squamous cell carcinoma treated at community cancer centers and receiving primary nonsurgical treatment was analyzed over time. Four-year overall survival was compared between community cancer centers and academic cancer centers. RESULTS: The majority (67.4%) of 20 298 patients were treated at an academic cancer center, yet the proportion of patients treated at community cancer centers increased by 10% from 2010 to 2019 (P < .01 for trend). The proportion of patients undergoing primary nonsurgical treatment increased from 62.1% to 73.7% from 2010 to 2019 (P < .01 for trend), and patients were statistically significantly more likely to undergo nonsurgical treatment at community cancer centers than at academic cancer centers (adjusted odds ratio = 1.20, 95% confidence interval = 1.18 to 1.22). Treatment at community cancer centers was associated with worse survival overall (adjusted hazard ratio = 1.19, 95% confidence interval = 1.09 to 1.31), specifically for patients receiving primary nonsurgical treatment (adjusted hazard ratio = 1.22, 95% confidence interval = 1.11 to 1.34). CONCLUSIONS: Treatment of HPV-related oropharyngeal squamous cell carcinoma has recently shifted to community cancer centers, with an increase in the proportion of nonsurgical treatment and worse overall survival at these centers compared with academic cancer centers. Concentration of care for HPV-related oropharyngeal squamous cell carcinoma at academic cancer centers and dedicated head and neck cancer centers may increase access to all available treatment modalities and improve survival.

Anatomical Variations of the Ascending Pharyngeal Artery: Implications for Endoscopic Surgery in the Parapharyngeal Space.

Objectives: The ascending pharyngeal artery (APA) travels with the parapharyngeal internal carotid artery (pICA) in the parapharyngeal space (PPS). This study aimed to investigate the anatomical variations of the APA, and to explore their implications for endoscopic surgery in the PPS. Methods: Dissection of the APA in the PPS was performed on 10 cadaveric specimens (20 sides). The relationship between APA and PPS tumors was retrospectively reviewed in 20 patients, attempting to ascertain the APA during the resection of 10 pre-styloid and 10 retro-styloid PPS tumors. Results: During the cadaveric dissections, the APA was identified at the medial, posteromedial, or bilateral aspects of the pICA in 12 (60%) and 4 (20%) sides, respectively. In the remaining 4 sides (20%), the APA branched into several subcategory arteries lying at the medial and lateral aspects of the pICA. Branches of the APA were observed in 13/20 sides (65%). Two branches were found in 9/13 sides and 3 branches in 4/13, respectively. The APA was only identifiable in 1/10 (10%) of pre-styloid tumors, a patient with basal cell adenoma. In contrast, the APA was encountered surrounding the pICA in 8/10 (80%) of patients with retro-styloid tumors, all of which were schwannomas. No inadvertent injury of the APA or the pICA occurred in this cohort. Conclusions: With identification of the ascending pharyngeal artery on preoperative magnetic resonance imaging, it may serve as an additional landmark during the endoscopic extirpation of tumors arising in the PPS.

International Consensus Statement on Allergy and Rhinology: Sinonasal Tumors.

BACKGROUND: Sinonasal neoplasms, whether benign and malignant, pose a significant challenge to clinicians and represent a model area for multidisciplinary collaboration in order to optimize patient care. The International Consensus Statement on Allergy and Rhinology: Sinonasal Tumors (ICSNT) aims to summarize the best available evidence and presents 48 thematic and histopathology-based topics spanning the field. METHODS: In accordance with prior International Consensus Statement on Allergy and Rhinology documents, ICSNT assigned each topic as an Evidence-Based Review with Recommendations, Evidence-Based Review, and Literature Review based on the level of evidence. An international group of multidisciplinary author teams were assembled for the topic reviews using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses format, and completed sections underwent a thorough and iterative consensus-building process. The final document underwent rigorous synthesis and review prior to publication. RESULTS: The ICSNT document consists of four major sections: general principles, benign neoplasms and lesions, malignant neoplasms, and quality of life and surveillance. It covers 48 conceptual and/or histopathology-based topics relevant to sinonasal neoplasms and masses. Topics with a high level of evidence provided specific recommendations, while other areas summarized the current state of evidence. A final section highlights research opportunities and future directions, contributing to advancing knowledge and community intervention. CONCLUSION: As an embodiment of the multidisciplinary and collaborative model of care in sinonasal neoplasms and masses, ICSNT was designed as a comprehensive, international, and multidisciplinary collaborative endeavor. Its primary objective is to summarize the existing evidence in the field of sinonasal neoplasms and masses.

Relevance of the Internal Jugular Vein for Surgery in the Upper Parapharyngeal Space.

Objective: Tumors arising from the upper parapharyngeal space (UPPS) may have intimate relationships with the internal carotid artery (ICA) and the internal jugular vein (IJV). The significance of the ICA in UPPS has been sufficiently articulated, whereas the relevance of the IJV has not been addressed. This study aimed to assess the anatomical variations of the IJV within the UPPS, and to explore its implications for surgical procedures. Methods: An endoscopic dissection of the IJV was performed on 10 cadaveric specimens. In addition, 30 patients who underwent transoral or transcervical resection of UPPS tumors were retrospectively reviewed to characterize the IJV and its relation to the tumor. Results: On the cadaveric specimens, the IJV was located at the posteromedial and posterolateral aspects of the styloid process in 13 (65%) and 7 (35%) sides, respectively. In our clinical series, the IJV was not encountered in 18 patients with pre-styloid tumors. In 12 patients harboring retro-styloid tumors, the IJV was partially (n = 5) or completely (n = 7) compressed and was displaced into the posterolateral aspect of the tumor. The IJV was injured intraoperatively in 1 patient, requiring an immediate conversion to an open transcervical corridor that allowed its exposure and ligation without difficulty. Conclusion: This study characterizes the IJV and its relationship with adjacent neurovascular structures in the UPPS, which may provide further safeguards during transoral and transcervical procedures in the UPPS.

Recurrent Nasopharyngeal Carcinoma and the Role of Surgery.

Recurrent nasopharyngeal carcinoma (rNPC) presents unique challenges as reirradiation comes with significant treatment-related morbidity in swallowing, middle ear function, and large-vessel integrity. Advances in endoscopic technology have made surgery for rNPC an increasingly viable option for select patients and may play a role in providing a better quality of life to patients with this challenging disease. In carefully selected patients, endoscopic and open surgical approaches may provide comparable disease control while mitigating long-term treatment-related morbidity.

Evaluation of the Incidence of Human Papillomavirus-Associated Squamous Cell Carcinoma of the Sinonasal Tract Among US Adults.

This case series assesses the incidence of human papillomavirus (HPV)-associated sinonasal squamous cell carcinoma (SNSCC) and the prevalence of HPV-positive SNSCC among US adults.

Translocations and Gene Fusions in Sinonasal Malignancies.

PURPOSE OF REVIEW: During the past few years there has been an expansion in our understanding of gene fusions and translocations involved in cancer of the sinonasal tract. Here we review the downstream biologic effects, clinical characteristics, and pathologic features of these tumors. The molecular consequences and neo-antigens resulting from these chromosomal aberrations are considered and targets for current and future clinical trials discussed. RECENT FINDINGS: Several new, clinically relevant, chromosomal aberrations have been discovered and evaluated to varying degrees in sinonasal tumors including DEK::AFF2, BRD4::NUT, ADCK4::NUMBL, and ETV6::NTRK3. Sinonasal malignancies demonstrate a diverse genetic landscape and varying clinical courses. Recent studies illustrate that gene fusions and translocations may play a role in carcinogenesis in certain sinonasal tumor subtypes and may be used to develop new biomarker-driven and patient-centered treatments.

Patient reported outcomes and treatment satisfaction in patients with cushing syndrome.

PURPOSE: Cushing Syndrome (CS) is a rare endocrine disorder associated with physical and mental symptoms that can drastically affect quality of life (QoL). This study characterizes QoL in patients with CS, describes their treatment experiences, and identifies patient subsets associated with decreased QoL or shared impressions of treatment. METHODS: A 136-question survey addressing QoL factors and treatment experiences was completed by adult patients with CS from the Cushing Support and Research Foundation. Patient demographics, tumor characteristics, and treatment information were collected. Bivariate analyses were conducted to determine if patients' symptoms or treatment experiences were significantly associated with demographics or other variables. RESULTS: A total of 178 patients, predominantly female (94%) with mean age 53 years, completed the survey. Anxiety and/or depression (n = 163, 94%), loss of physical strength (n = 164, 93%), loneliness (n = 156, 90%), fatigue from treatment (n = 142, 89%), memory loss (n = 153, 88%), insomnia (n = 144, 83%), and pain (n = 141, 83%) were symptoms most commonly experienced by respondents. Patients experiencing delay of diagnosis >10 years were more likely to have suicidal thoughts (p = 0.002). Younger patients were more likely to express concerns about hair loss (p = 0.007), loneliness (p = 0.025), pain (p = 0.004), or the impact of CS on their marriage (p = 0.039) or children (p = 0.024). CONCLUSION: This survey demonstrates CS impacts patients across many dimensions, emphasizing the need for holistic support. We identified patient subsets in which QoL may be improved with additional patient resources or provider attention.

Endonasal Exposure of Lateral Recess of the Sphenoid Sinus: Significance of Pterygoid Process Pneumatization.

BACKGROUND: Caudal pneumatization of the pterygoid process may impact endonasal exposure of the lateral recess of sphenoid sinus (LRSS). OBJECTIVES: This study aims to explore the implications of a pneumatized pterygoid process for an endonasal transpterygoid approach to the LRSS and to define strategies regarding the preservation or sacrifice of the vidian nerve. METHODS: Dissection of the LRSS (11 sides) was performed on 6 cadaveric specimens, preselected for the radiographic presence of an LRSS. In addition, the dimensions of the LRSS were measured on the deidentified CT images of 120 patients (240 sides). The sphenoid sinus was subdivided into 3 categories: Type 1 (no identifiable LRSS), Type 2 (lateral pneumatization of the greater wing above the vidian canal), and Type 3 (pneumatization of both the greater wing and the pterygoid process). RESULTS: On the cadaveric specimens, a Type 2 pneumatization often allowed access to the LRSS above the level of the vidian canal; thus, sparing the vidian neurovascular bundle. In Type 3 pneumatization, a frontal corridor through the pterygoid base could be created to reach the LRSS with preservation of the vidian nerve. Extreme Type 3 pneumatization, however, required the transposition or sacrifice of the vidian nerve to facilitate a full direct access to the superolateral LRSS. Measurements on CT images revealed that the extent of caudal pneumatization of the pterygoid process had no statistically significant correlation with the superolateral extension of the lateral recess in patients with Type 3 LRSS (P > .05). CONCLUSION: Pneumatization of the LRSS toward a caudal or superolateral direction may develop independent from each other. Caudal pneumatization of the pterygoid process seems to variably impact the endonasal exposure of the LRSS.

Endoscopic transoral approach to the lateral poststyloid space.

The lateral poststyloid space (LPSS) located at the posterolateral aspect of the styloid process. This study aims to explore the anatomical relationships in LPSS via a transoral corridor, providing reference for addressing lesions extending to this region. An endoscopic transoral approach for exposure of the LPSS was performed on 6 cadaveric specimens (12 sides). Related landmarks were explored, and transoral extirpation of tumors extended into LPSS was employed in 12 patients. The deep lobe of the parotid gland, extratemporal facial nerve, and the accompanying artery in the LPSS were sufficiently exposed via the transoral corridor in all 12 cadaveric sides. The transoral corridor provided adequate exposure for tumors extending to the LPSS, and en bloc resection was achieved in these 12 patients. No facial nerve or vascular injury occurred, and no recurrence observed in this cohort with an average follow-up of 26 months. An endoscopic transoral approach provides a direct access to the LPSS. Appreciation of the anatomical relationships within the LPSS is valuable for employing a transoral extirpation of tumors extending to this specific region.

Reconstruction in open anterior skull base surgery: A review and algorithmic approach.

PURPOSE: Defects resulting from open resection of anterior skull base neoplasms are difficult to reconstruct. Our objective was to review the literature and describe an evidence-based algorithm that can guide surgeons reconstructing anterior skull base defects. METHODS: A research librarian designed database search strategies. Two investigators independently reviewed the resulting abstracts and full text articles. Studies on reconstruction after open anterior skull base resection were included. Studies of lateral and posterior skull base reconstruction, endoscopic endonasal surgery, traumatic and congenital reconstruction were excluded. Based on the review, a reconstructive algorithm was proposed. RESULTS: The search strategy identified 603 unique abstracts. 53 articles were included. Adjacent subsites resected, defect size, radiotherapy history, and contraindications to free tissue transfer were identified as key factors influencing decision making and were used to develop the algorithm. Discussion of the reconstructive ladder as it applies to skull base reconstruction and consideration of patient specific factors are reviewed. Patients with a prior history of radiotherapy or with simultaneous resection of multiple anatomic subsites adjacent to the anterior skull base will likely benefit from free tissue transfer. CONCLUSIONS: Reconstruction of anterior skull base defects requires knowledge of the available reconstructive techniques and consideration of defect-specific and patient-specific factors.

Resection of Carotid Body Tumors in Patients of Advanced Age: Experience From a Single Center.

INTRODUCTION: Resection of carotid body tumor (CBT) in patients of advanced ages has not been appreciated. OBJECTIVES: This study aims to assess the clinical characteristics and perioperative comorbidities for CBT resection in patients of advanced age and to validate the application of an "isolated island" technique for extirpation of CBT. METHODS: Eight patients of advanced age (≥60 years) who underwent CBT resection were enrolled as the study group (SG). Another 29 patients of younger age (<45 years old) underwent CBT extirpation were assigned as the control group (CG). The perioperative issues were compared between these 2 groups. RESULTS: The "isolated island" technique was successfully applied for resection of CBT in all 37 patients. The prevalence of Shamblin classification I, II, and III tumors in the SG was 12.5%, 62.5%, and 25%; whereas in the CG was 10.3%, 55.2%, and 34.5%, respectively. Bilateral CBT was observed in 7 patients of the CG and none in the SG. Vascular reconstruction was required for 1 (12.5%) patient in the SG, while it was required for 8 (27.6%) patients in the CG. Postoperative vocal cord palsy occurred in 37.5% of patients in SG, whereas the vocal cord palsy (34.5%) and dysphagia (6.9%) were commonly encountered in CG. In addition to postoperative length of stay (P = .004), no significant difference for operative time, intraoperative blood loss, or mortality were observed between these 2 groups (P > .05). CONCLUSION: Extirpation of CBT in patients of advanced age is rationale in appropriately selected patients. The "isolated island" technique is safe for CBT resection with seemingly low complication rates.

Management of Multiple Head and Neck Paragangliomas With Assistance of a 3-D Model.

INTRODUCTION: Extirpation of multiple head and neck paragangliomas carries challenge due to close anatomic relationships with critical neurovascular bundles. OBJECTIVES: This study aims to assess whether the application of 3-D models can assist with surgical planning and treatment of these paragangliomas, decrease surgically related morbidity and mortality. METHODS: Fourteen patients undergoing surgical resection of multiple head and neck paragangliomas were enrolled in this study. A preoperative 3-D model was created based on radiologic data, and relevant critical anatomic relationships were preoperatively assessed and intraoperatively validated. RESULTS: All 14 patients presented with multiple head and neck paragangliomas, including bilateral carotid body tumors (CBT, n = 9), concurrent CBT with glomus jugulare tumors (GJT, n = 4), and multiple vagal paragangliomas (n = 1). Ten patients underwent genomic analysis and all harbored succinate dehydrogenase complex subunit D (SDHD) mutations. Under guidance of the 3-D model, the internal carotid artery (ICA) was circumferentially encased by tumor on 5 of the operated sides, in 4 (80%) of which the tumor was successfully dissected out from the ICA, whereas ICA reconstruction was required on one side (20%). Following removal of CBT, anterior rerouting of the facial nerve was avoided in 3 (75%) of 4 patients during the extirpation of GJT with assistance of a 3-D model. Two patients developed permanent postoperative vocal cord paralysis. There was no vessel rupture or mortality in this study cohort. CONCLUSION: The 3-D model is beneficial for establishment of a preoperative strategy, as well as planning and guiding the intraoperative procedure for resection of multiple head and neck paragangliomas.

Exploiting the immunogenic potential of standard of care radiation or cisplatin therapy in preclinical models of HPV-associated malignancies.

BACKGROUND: While radiation and chemotherapy are primarily purposed for their cytotoxic effects, a growing body of preclinical and clinical evidence demonstrates an immunogenic potential for these standard therapies. Accordingly, we sought to characterize the immunogenic potential of radiation and cisplatin in human tumor models of HPV-associated malignancies. These studies may inform rational combination immuno-oncology (IO) strategies to be employed in the clinic on the backbone of standard of care, and in so doing exploit the immunogenic potential of standard of care to improve durable responses in HPV-associated malignancies. METHODS: Retroviral transduction with HPV16 E7 established a novel HPV-associated sinonasal squamous cell carcinoma (SNSCC) cell line. Three established HPV16-positive cell lines were also studied (cervical carcinoma and head and neck squamous cell carcinoma). Following determination of sensitivities to standard therapies using MTT assays, flow cytometry was used to characterize induction of immunogenic cell stress following sublethal exposure to radiation or cisplatin, and the functional consequence of this induction was determined using impedance-based real time cell analysis cytotoxicity assays employing HPV16 E7-specific cytotoxic lymphocytes (CTLs) with or without N803 (IL-15/IL-15-Rα superagonist) or exogenous death receptor ligands. In vitro observations were translated using an in vivo xenograft NSG mouse model of human cervical carcinoma evaluating cisplatin in combination with CTL adoptive cell transfer. RESULTS: We showed that subpopulations surviving clinically relevant doses of radiation or cisplatin therapy were more susceptible to CTL-mediated lysis in four of four tumor models of HPV-associated malignancies, serving as a model for HPV therapeutic vaccine or T-cell receptor adoptive cell transfer. This increased killing was further amplified by IL-15 agonism employing N803. We further characterized that radiation or cisplatin induced immunogenic cell stress in three of three cell lines, and consequently demonstrated that upregulated surface expression of Fas and TRAIL-R2 death receptors at least in part mediated enhanced CTL-mediated lysis. In vivo, cisplatin-induced immunogenic cell stress synergistically potentiated CTL-mediated tumor control in a human model of HPV-associated malignancy. CONCLUSION: Standard of care radiation or cisplatin therapy induced immunogenic cell stress in preclinical models of HPV-associated malignancies, presenting an opportunity poised for exploitation by employing IO strategies in combination with standard of care.