Oropharyngeal cancer outcomes correlate with p16 status, multinucleation and immune infiltration

David C. Wilde; Patricia D. Castro; Kaustav Bera; Syeling Lai; Anant Madabhushi; German Corredor; Can Koyuncu; James S. Lewis; Cheng Lu; Mitchell J. Frederick; Allan M. Frederick; Avery E. Haugen; Jose P. Zevallos; Erich M. Sturgis; Justin Shi; Andrew T. Huang; David J. Hernandez; Heath D. Skinner; Jan O. Kemnade; Wendong Yu; Andrew G. Sikora; Vlad C. Sandulache

doi:10.1038/s41379-022-01024-8

Oropharyngeal cancer outcomes correlate with p16 status, multinucleation and immune infiltration

David C. Wilde, Patricia D. Castro, Kaustav Bera, Syeling Lai, Anant Madabhushi, German Corredor, Can Koyuncu, James S. Lewis, Cheng Lu, Mitchell J. Frederick, Allan M. Frederick, Avery E. Haugen, Jose P. Zevallos, Erich M. Sturgis, Justin Shi, Andrew T. Huang, David J. Hernandez, Heath D. Skinner, Jan O. Kemnade, Wendong YuAndrew G. Sikora, Vlad C. Sandulache

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21 Scopus citations

Abstract

Oropharyngeal squamous cell carcinoma (OPSCC), largely fueled by the human papillomavirus (HPV), has a complex biological and immunologic phenotype. Although HPV/p16 status can be used to stratify OPSCC patients as a function of survival, it remains unclear what drives an improved treatment response in HPV-associated OPSCC and whether targetable biomarkers exist that can inform a precision oncology approach. We analyzed OPSCC patients treated between 2000 and 2016 and correlated locoregional control (LRC), disease-free survival (DFS) and overall survival (OS) with conventional clinical parameters, risk parameters generated using deep-learning algorithms trained to quantify tumor-infiltrating lymphocytes (TILs) (OP-TIL) and multinucleated tumor cells (MuNI) and targeted transcriptomics. P16 was a dominant determinant of LRC, DFS and OS, but tobacco exposure, OP-TIL and MuNI risk features correlated with clinical outcomes independent of p16 status and the combination of p16, OP-TIL and MuNI generated a better stratification of OPSCC risk compared to individual parameters. Differential gene expression (DEG) analysis demonstrated overlap between MuNI and OP-TIL and identified genes involved in DNA repair, oxidative stress response and tumor immunity as the most prominent correlates with survival. Alteration of inflammatory/immune pathways correlated strongly with all risk features and oncologic outcomes. This suggests that development of OPSCC consists of an intersection between multiple required and permissive oncogenic and immunologic events which may be mechanistically linked. The strong relationship between tumor immunity and oncologic outcomes in OPSCC regardless of HPV status may provide opportunities for further biomarker development and precision oncology approaches incorporating immune checkpoint inhibitors for maximal anti-tumor efficacy.

Original language	English
Pages (from-to)	1045-1054
Number of pages	10
Journal	Modern Pathology
Volume	35
Issue number	8
DOIs	https://doi.org/10.1038/s41379-022-01024-8
State	Published - Aug 2022

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Wilde, D. C., Castro, P. D., Bera, K., Lai, S., Madabhushi, A., Corredor, G., Koyuncu, C., Lewis, J. S., Lu, C., Frederick, M. J., Frederick, A. M., Haugen, A. E., Zevallos, J. P., Sturgis, E. M., Shi, J., Huang, A. T., Hernandez, D. J., Skinner, H. D., Kemnade, J. O., ... Sandulache, V. C. (2022). Oropharyngeal cancer outcomes correlate with p16 status, multinucleation and immune infiltration. Modern Pathology, 35(8), 1045-1054. https://doi.org/10.1038/s41379-022-01024-8

@article{91641286ac6c49ae9eea3c08f7488d7a,

title = "Oropharyngeal cancer outcomes correlate with p16 status, multinucleation and immune infiltration",

abstract = "Oropharyngeal squamous cell carcinoma (OPSCC), largely fueled by the human papillomavirus (HPV), has a complex biological and immunologic phenotype. Although HPV/p16 status can be used to stratify OPSCC patients as a function of survival, it remains unclear what drives an improved treatment response in HPV-associated OPSCC and whether targetable biomarkers exist that can inform a precision oncology approach. We analyzed OPSCC patients treated between 2000 and 2016 and correlated locoregional control (LRC), disease-free survival (DFS) and overall survival (OS) with conventional clinical parameters, risk parameters generated using deep-learning algorithms trained to quantify tumor-infiltrating lymphocytes (TILs) (OP-TIL) and multinucleated tumor cells (MuNI) and targeted transcriptomics. P16 was a dominant determinant of LRC, DFS and OS, but tobacco exposure, OP-TIL and MuNI risk features correlated with clinical outcomes independent of p16 status and the combination of p16, OP-TIL and MuNI generated a better stratification of OPSCC risk compared to individual parameters. Differential gene expression (DEG) analysis demonstrated overlap between MuNI and OP-TIL and identified genes involved in DNA repair, oxidative stress response and tumor immunity as the most prominent correlates with survival. Alteration of inflammatory/immune pathways correlated strongly with all risk features and oncologic outcomes. This suggests that development of OPSCC consists of an intersection between multiple required and permissive oncogenic and immunologic events which may be mechanistically linked. The strong relationship between tumor immunity and oncologic outcomes in OPSCC regardless of HPV status may provide opportunities for further biomarker development and precision oncology approaches incorporating immune checkpoint inhibitors for maximal anti-tumor efficacy.",

author = "Wilde, {David C.} and Castro, {Patricia D.} and Kaustav Bera and Syeling Lai and Anant Madabhushi and German Corredor and Can Koyuncu and Lewis, {James S.} and Cheng Lu and Frederick, {Mitchell J.} and Frederick, {Allan M.} and Haugen, {Avery E.} and Zevallos, {Jose P.} and Sturgis, {Erich M.} and Justin Shi and Huang, {Andrew T.} and Hernandez, {David J.} and Skinner, {Heath D.} and Kemnade, {Jan O.} and Wendong Yu and Sikora, {Andrew G.} and Sandulache, {Vlad C.}",

note = "Publisher Copyright: {\textcopyright} 2022, The Author(s), under exclusive licence to United States & Canadian Academy of Pathology.",

year = "2022",

month = aug,

doi = "10.1038/s41379-022-01024-8",

language = "English",

volume = "35",

pages = "1045--1054",

journal = "Modern Pathology",

issn = "0893-3952",

number = "8",

}

Wilde, DC, Castro, PD, Bera, K, Lai, S, Madabhushi, A, Corredor, G, Koyuncu, C, Lewis, JS, Lu, C, Frederick, MJ, Frederick, AM, Haugen, AE, Zevallos, JP, Sturgis, EM, Shi, J, Huang, AT, Hernandez, DJ, Skinner, HD, Kemnade, JO, Yu, W, Sikora, AG & Sandulache, VC 2022, 'Oropharyngeal cancer outcomes correlate with p16 status, multinucleation and immune infiltration', Modern Pathology, vol. 35, no. 8, pp. 1045-1054. https://doi.org/10.1038/s41379-022-01024-8

TY - JOUR

T1 - Oropharyngeal cancer outcomes correlate with p16 status, multinucleation and immune infiltration

AU - Wilde, David C.

AU - Castro, Patricia D.

AU - Bera, Kaustav

AU - Lai, Syeling

AU - Madabhushi, Anant

AU - Corredor, German

AU - Koyuncu, Can

AU - Lewis, James S.

AU - Lu, Cheng

AU - Frederick, Mitchell J.

AU - Frederick, Allan M.

AU - Haugen, Avery E.

AU - Zevallos, Jose P.

AU - Sturgis, Erich M.

AU - Shi, Justin

AU - Huang, Andrew T.

AU - Hernandez, David J.

AU - Skinner, Heath D.

AU - Kemnade, Jan O.

AU - Yu, Wendong

AU - Sikora, Andrew G.

AU - Sandulache, Vlad C.

PY - 2022/8

Y1 - 2022/8

N2 - Oropharyngeal squamous cell carcinoma (OPSCC), largely fueled by the human papillomavirus (HPV), has a complex biological and immunologic phenotype. Although HPV/p16 status can be used to stratify OPSCC patients as a function of survival, it remains unclear what drives an improved treatment response in HPV-associated OPSCC and whether targetable biomarkers exist that can inform a precision oncology approach. We analyzed OPSCC patients treated between 2000 and 2016 and correlated locoregional control (LRC), disease-free survival (DFS) and overall survival (OS) with conventional clinical parameters, risk parameters generated using deep-learning algorithms trained to quantify tumor-infiltrating lymphocytes (TILs) (OP-TIL) and multinucleated tumor cells (MuNI) and targeted transcriptomics. P16 was a dominant determinant of LRC, DFS and OS, but tobacco exposure, OP-TIL and MuNI risk features correlated with clinical outcomes independent of p16 status and the combination of p16, OP-TIL and MuNI generated a better stratification of OPSCC risk compared to individual parameters. Differential gene expression (DEG) analysis demonstrated overlap between MuNI and OP-TIL and identified genes involved in DNA repair, oxidative stress response and tumor immunity as the most prominent correlates with survival. Alteration of inflammatory/immune pathways correlated strongly with all risk features and oncologic outcomes. This suggests that development of OPSCC consists of an intersection between multiple required and permissive oncogenic and immunologic events which may be mechanistically linked. The strong relationship between tumor immunity and oncologic outcomes in OPSCC regardless of HPV status may provide opportunities for further biomarker development and precision oncology approaches incorporating immune checkpoint inhibitors for maximal anti-tumor efficacy.

AB - Oropharyngeal squamous cell carcinoma (OPSCC), largely fueled by the human papillomavirus (HPV), has a complex biological and immunologic phenotype. Although HPV/p16 status can be used to stratify OPSCC patients as a function of survival, it remains unclear what drives an improved treatment response in HPV-associated OPSCC and whether targetable biomarkers exist that can inform a precision oncology approach. We analyzed OPSCC patients treated between 2000 and 2016 and correlated locoregional control (LRC), disease-free survival (DFS) and overall survival (OS) with conventional clinical parameters, risk parameters generated using deep-learning algorithms trained to quantify tumor-infiltrating lymphocytes (TILs) (OP-TIL) and multinucleated tumor cells (MuNI) and targeted transcriptomics. P16 was a dominant determinant of LRC, DFS and OS, but tobacco exposure, OP-TIL and MuNI risk features correlated with clinical outcomes independent of p16 status and the combination of p16, OP-TIL and MuNI generated a better stratification of OPSCC risk compared to individual parameters. Differential gene expression (DEG) analysis demonstrated overlap between MuNI and OP-TIL and identified genes involved in DNA repair, oxidative stress response and tumor immunity as the most prominent correlates with survival. Alteration of inflammatory/immune pathways correlated strongly with all risk features and oncologic outcomes. This suggests that development of OPSCC consists of an intersection between multiple required and permissive oncogenic and immunologic events which may be mechanistically linked. The strong relationship between tumor immunity and oncologic outcomes in OPSCC regardless of HPV status may provide opportunities for further biomarker development and precision oncology approaches incorporating immune checkpoint inhibitors for maximal anti-tumor efficacy.

UR - http://www.scopus.com/inward/record.url?scp=85124835777&partnerID=8YFLogxK

U2 - 10.1038/s41379-022-01024-8

DO - 10.1038/s41379-022-01024-8

M3 - Article

C2 - 35184149

AN - SCOPUS:85124835777

SN - 0893-3952

VL - 35

SP - 1045

EP - 1054

JO - Modern Pathology

JF - Modern Pathology

IS - 8

ER -

Oropharyngeal cancer outcomes correlate with p16 status, multinucleation and immune infiltration

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