TY - JOUR
T1 - Cervical cancer neoantigen landscape and immune activity is associated with human papillomavirus master regulators
AU - Qin, Yong
AU - Ekmekcioglu, Suhendan
AU - Forget, Marie Andrée
AU - Szekvolgyi, Lorant
AU - Hwu, Patrick
AU - Grimm, Elizabeth A.
AU - Jazaeri, Amir A.
AU - Roszik, Jason
N1 - Publisher Copyright:
© 2017 Qin, Ekmekcioglu, Forget, Szekvolgyi, Hwu, Grimm, Jazaeri and Roszik.
PY - 2017/6/16
Y1 - 2017/6/16
N2 - Human papillomaviruses (HPVs) play a major role in development of cervical cancer, and HPV oncoproteins are being targeted by immunotherapies. Although these treatments show promising results in the clinic, many patients do not benefit or the durability is limited. In addition to HPV antigens, neoantigens derived from somatic mutations may also generate an effective immune response and represent an additional and distinct immunotherapy strategy against this and other HPV-associated cancers. To explore the landscape of neoantigens in cervix cancer, we predicted all possible mutated neopeptides in two large sequencing data sets and analyzed whether mutation and neoantigen load correlate with antigen presentation, infiltrating immune cell types, and a HPV-induced master regulator gene expression signature. We found that targetable neoantigens are detected in most tumors, and there are recurrent mutated peptides from known oncogenic driver genes (KRAS, MAPK1, PIK3CA, ERBB2, and ERBB3) that are predicted to be potentially immunogenic. Our studies show that HPV-induced master regulators are not only associated with HPV load but may also play crucial roles in relation to mutation and neoantigen load, and also the immune microenvironment of the tumor. A subset of these HPV-induced master regulators positively correlated with expression of immune-suppressor molecules such as PD-L1, TGFB1, and IL-10 suggesting that they may be involved in abrogating antitumor response induced by the presence of mutations and neoantigens. Based on these results, we predict that HPV master regulators identified in our study might be potentially effective targets in cervical cancer.
AB - Human papillomaviruses (HPVs) play a major role in development of cervical cancer, and HPV oncoproteins are being targeted by immunotherapies. Although these treatments show promising results in the clinic, many patients do not benefit or the durability is limited. In addition to HPV antigens, neoantigens derived from somatic mutations may also generate an effective immune response and represent an additional and distinct immunotherapy strategy against this and other HPV-associated cancers. To explore the landscape of neoantigens in cervix cancer, we predicted all possible mutated neopeptides in two large sequencing data sets and analyzed whether mutation and neoantigen load correlate with antigen presentation, infiltrating immune cell types, and a HPV-induced master regulator gene expression signature. We found that targetable neoantigens are detected in most tumors, and there are recurrent mutated peptides from known oncogenic driver genes (KRAS, MAPK1, PIK3CA, ERBB2, and ERBB3) that are predicted to be potentially immunogenic. Our studies show that HPV-induced master regulators are not only associated with HPV load but may also play crucial roles in relation to mutation and neoantigen load, and also the immune microenvironment of the tumor. A subset of these HPV-induced master regulators positively correlated with expression of immune-suppressor molecules such as PD-L1, TGFB1, and IL-10 suggesting that they may be involved in abrogating antitumor response induced by the presence of mutations and neoantigens. Based on these results, we predict that HPV master regulators identified in our study might be potentially effective targets in cervical cancer.
KW - Cervical cancer
KW - Human papillomavirus
KW - Immunotherapy
KW - Master regulators
KW - Neoantigens
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U2 - 10.3389/fimmu.2017.00689
DO - 10.3389/fimmu.2017.00689
M3 - Article
C2 - 28670312
AN - SCOPUS:85021185202
SN - 1664-3224
VL - 8
JO - Frontiers in immunology
JF - Frontiers in immunology
IS - JUN
M1 - 689
ER -