HPV-Positive and -Negative Cervical Cancers Are Immunologically Distinct

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), HPV α7 species (HPV18-like) and HPV-negative disease. HPV-negative CC appeared distinct from other subtypes, with greatly reduced levels of lymphocyte infiltration compared to either HPV α9 or α7 CC. Besides reduced levels of markers indicative of B, T, and NK lymphocytes, the expression of T-cell effector molecules, activation/exhaustion markers, and T-cell receptor diversity were also significantly lower in HPV-negative CC. Interestingly, HPV-negative CC expressed much higher levels of potential neoantigens than HPV-positive CC. These results identify profound differences between the immune landscape of HPV-positive and HPV-negative CC as well as modest differences between HPV α9 and α7 CC. These differences may contribute to altered patient outcomes between HPV-negative and HPV-positive CC and potentially between CC associated with different HPV types.

Reduced MHC Class I and II Expression in HPV−Negative vs. HPV−Positive Cervical 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.…”

“…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 ].…”

“…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.…”

“…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.…”

“…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.…”