Abstract:Although infection with human papillomavirus (HPV) is associated with nearly all cervical cancers (CC), a small proportion are HPV-negative. Recently, it has become clear that HPV-negative CC represent a distinct disease phenotype compared to HPV-positive disease and exhibit increased mortality. In addition, variations between different HPV types associated with CC have been linked to altered molecular pathology and prognosis. We compared the immune microenvironments of CC caused by HPV α9 species (HPV16-like)… Show more
“…Despite the well-recognized distinctions between both the pathology [ 32 , 33 ] and clinical outcomes of HPV+ and HPV− CC, few studies have directly compared aspects of the tumor immune microenvironment between these etiologically distinct cancers of the cervix [ 29 ]. Furthermore, the small proportion of HPV− CC compared to HPV+ CC limits the statistical power of tests used to compare them.…”
Section: Discussionmentioning
confidence: 99%
“…Our comparison of RNA-seq data for genes involved in both the MHC class I and MHC class II pathways identified an overall trend in increased expression of these genes in HPV+ CC compared to HPV− CC. This likely reflects the “hotter” TME of HPV+ CC since, like other virus-induced cancers, they exhibit increased levels of IFNγ, as well as higher MHC class I and II expression [ 25 , 27 , 28 , 29 , 66 , 67 , 68 ].…”
Section: Discussionmentioning
confidence: 99%
“…APOBEC-mediated mutations appear to occur at a later stage of tumor evolution, and the rate of APOBEC mutation has been positively correlated with increased expression of mutation-induced neoantigens, which may drive the host immune response [ 95 ]. Despite the higher expression of APOBEC3A , 3B , and 3H in HPV+ CC compared to HPV− CC ( Figure S3 ), there appears to be a higher level of predicted neoantigens in HPV− CC, indicating that these neoantigens may not be induced through the activity of APOBEC3 [ 29 ]. Therefore, it is still unclear if and how the higher expression of APOBEC3-related genes, likely induced by the proinflammatory environment within HPV+ CC, may change the tumor microenvironment of these cancers compared to HPV− CC.…”
Section: Discussionmentioning
confidence: 99%
“…mRNA expression comparisons were analyzed as carried out previously [ 29 , 42 , 43 ]. Level 3 RNA-Seq by Expectation Maximization (RSEM) normalized Illumina HiSeq RNA expression data for the TCGA CC cohort were downloaded as described above.…”
Section: Methodsmentioning
confidence: 99%
“…These HPV+ HNSCC tumors also demonstrate higher expression of MHC class I- and II-related genes compared to HPV− tumors [ 27 , 28 ]. We have recently identified higher levels of tumor-infiltrating lymphocytes and other factors indicative of a more immune-hot phenotype in HPV+ CC compared to HPV− CC [ 29 ]. These differences between the TME of HPV+ and HPV− CC may have implications for the outcomes of these cancers.…”
Cervical cancer (CC) is the second most common cancer in women worldwide and the fourth leading cause of cancer-associated death in women. Although human papillomavirus (HPV) infection is associated with nearly all CC, it has recently become clear that HPV−negative (HPV−) CC represents a distinct disease phenotype with increased mortality. HPV−positive (HPV+) and HPV− CC demonstrate different molecular pathology, prognosis, and response to treatment. Furthermore, CC caused by HPV α9 types (HPV16-like) often have better outcomes than those caused by HPV α7 types (HPV18-like). This study systematically and comprehensively compared the expression of genes involved in major histocompatibility complex (MHC) class I and II presentation within CC caused by HPV α9 types, HPV α7 types, and HPV− CC. We observed increased expression of MHC class I and II classical and non-classical genes in HPV+ CC and overall higher expression of genes involved in their antigen loading and presentation apparatus as well as transcriptional regulation. Increased expression of MHC I-related genes differs from previous studies using cell culture models. These findings identify crucial differences between antigen presentation within the tumor immune microenvironments of HPV+ and HPV− CC, as well as modest differences between HPV α9 and α7 CC. These differences may contribute to the altered patient outcomes and responses to immunotherapy observed between these distinct cancers.
“…Despite the well-recognized distinctions between both the pathology [ 32 , 33 ] and clinical outcomes of HPV+ and HPV− CC, few studies have directly compared aspects of the tumor immune microenvironment between these etiologically distinct cancers of the cervix [ 29 ]. Furthermore, the small proportion of HPV− CC compared to HPV+ CC limits the statistical power of tests used to compare them.…”
Section: Discussionmentioning
confidence: 99%
“…Our comparison of RNA-seq data for genes involved in both the MHC class I and MHC class II pathways identified an overall trend in increased expression of these genes in HPV+ CC compared to HPV− CC. This likely reflects the “hotter” TME of HPV+ CC since, like other virus-induced cancers, they exhibit increased levels of IFNγ, as well as higher MHC class I and II expression [ 25 , 27 , 28 , 29 , 66 , 67 , 68 ].…”
Section: Discussionmentioning
confidence: 99%
“…APOBEC-mediated mutations appear to occur at a later stage of tumor evolution, and the rate of APOBEC mutation has been positively correlated with increased expression of mutation-induced neoantigens, which may drive the host immune response [ 95 ]. Despite the higher expression of APOBEC3A , 3B , and 3H in HPV+ CC compared to HPV− CC ( Figure S3 ), there appears to be a higher level of predicted neoantigens in HPV− CC, indicating that these neoantigens may not be induced through the activity of APOBEC3 [ 29 ]. Therefore, it is still unclear if and how the higher expression of APOBEC3-related genes, likely induced by the proinflammatory environment within HPV+ CC, may change the tumor microenvironment of these cancers compared to HPV− CC.…”
Section: Discussionmentioning
confidence: 99%
“…mRNA expression comparisons were analyzed as carried out previously [ 29 , 42 , 43 ]. Level 3 RNA-Seq by Expectation Maximization (RSEM) normalized Illumina HiSeq RNA expression data for the TCGA CC cohort were downloaded as described above.…”
Section: Methodsmentioning
confidence: 99%
“…These HPV+ HNSCC tumors also demonstrate higher expression of MHC class I- and II-related genes compared to HPV− tumors [ 27 , 28 ]. We have recently identified higher levels of tumor-infiltrating lymphocytes and other factors indicative of a more immune-hot phenotype in HPV+ CC compared to HPV− CC [ 29 ]. These differences between the TME of HPV+ and HPV− CC may have implications for the outcomes of these cancers.…”
Cervical cancer (CC) is the second most common cancer in women worldwide and the fourth leading cause of cancer-associated death in women. Although human papillomavirus (HPV) infection is associated with nearly all CC, it has recently become clear that HPV−negative (HPV−) CC represents a distinct disease phenotype with increased mortality. HPV−positive (HPV+) and HPV− CC demonstrate different molecular pathology, prognosis, and response to treatment. Furthermore, CC caused by HPV α9 types (HPV16-like) often have better outcomes than those caused by HPV α7 types (HPV18-like). This study systematically and comprehensively compared the expression of genes involved in major histocompatibility complex (MHC) class I and II presentation within CC caused by HPV α9 types, HPV α7 types, and HPV− CC. We observed increased expression of MHC class I and II classical and non-classical genes in HPV+ CC and overall higher expression of genes involved in their antigen loading and presentation apparatus as well as transcriptional regulation. Increased expression of MHC I-related genes differs from previous studies using cell culture models. These findings identify crucial differences between antigen presentation within the tumor immune microenvironments of HPV+ and HPV− CC, as well as modest differences between HPV α9 and α7 CC. These differences may contribute to the altered patient outcomes and responses to immunotherapy observed between these distinct cancers.
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