Reduced MHC Class I and II Expression in HPV-Negative vs. HPV-Positive Cervical Cancers

Abstract

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.

Keywords: T cell; The Cancer Genome Atlas (TCGA); cervical cancer (CC); gene expression; human papillomavirus (HPV); major histocompatibility complex (MHC).

Figure 1

Expression of classical MHC class II α- and β-chain genes in CC stratified by HPV+ (α9 or α7) and HPV− status. Normalized RNA-seq data were extracted from the CC cohort of the TCGA database. *** p ≤ 0.001, ** p ≤ 0.01, * p ≤ 0.05, ns (not significant).

Figure 2

Expression of invariant chain (CD74) and MHC class II-like genes in CC stratified by HPV+ (α9 or α7) and HPV− status. Normalized RNA-seq data were extracted from the CC cohort of the TCGA database. *** p ≤ 0.001, ** p ≤ 0.01, * p ≤ 0.05, ns (not significant).

Figure 3

Expression of transcriptional regulators of MHC class II and IFNγ in CC stratified by HPV+ (α9 or α7) and HPV− status. Normalized RNA-seq data for CIITA, genes encoding for the RFX family of transcription factors, and IFNγ were extracted from the CC cohort of the TCGA database. *** p ≤ 0.001, ** p ≤ 0.01, * p ≤ 0.05, ns (not significant).

Figure 4

Expression of genes that encode for T cell co-stimulatory and activation molecules in CC stratified by HPV+ (α9 or α7) and HPV− status. Normalized RNA-seq data for genes encoding important costimulatory molecules and T cell activation markers were extracted from the CC cohort of the TCGA database. *** p ≤ 0.001, ** p ≤ 0.01, * p ≤ 0.05, ns (not significant).

Figure 5

Expression of MHC class I classical and non-classical heavy chain genes in CC stratified by HPV+ (α9 or α7) and HPV− status. Normalized RNA-seq data for MHC class I classical and non-classical were extracted from the CC cohort of the TCGA database. *** p ≤ 0.001, ** p ≤ 0.01, * p ≤ 0.05, ns (not significant).

Figure 6

Expression of MHC class I light chain and other genes involved in antigen loading and presentation in CC stratified by HPV+ (α9 or α7) and HPV− status. Normalized RNA-seq data for B2M as well as genes important in the MHC class I antigen presentation pathway were extracted from the CC cohort of the TCGA database. *** p ≤ 0.001, ** p ≤ 0.01, * p ≤ 0.05, ns (not significant).

Figure 7

Expression of transcriptional regulators involved in MHC class I expression in CC stratified by HPV+ (α9 or α7) and HPV− status. Normalized RNA-seq data for key transcriptional regulators of MHC class I expression as well as genes in the NF-κB transcription factor family were extracted from the CC cohort of the TCGA database. *** p ≤ 0.001, ** p ≤ 0.01, * p ≤ 0.05, ns (not significant).