Increased HLA-DMB Expression in the Tumor Epithelium Is Associated with Increased CTL Infiltration and Improved Prognosis in Advanced-Stage Serous Ovarian Cancer

Abstract

Purpose: To evaluate the possible mechanisms influencing the infiltration of CD8 T lymphocytes into the tumor epithelium of advanced-stage serous ovarian cancers. Experimental Design: Immunohistochemical localization of CD8 T lymphocytes was done on a homogeneous population of 184 high-grade, advanced-stage serous ovarian cancer tissue specimens. Microarray analysis was done on microdissected tumor epithelium from 38 specimens to identify genes up-regulated or down-regulated in specimens with differing numbers of tumor-infiltrating CD8 T lymphocytes. Quantitative real-time PCR and immunohistochemistry were used to validate a candidate gene. Univariate and multivariate survival analyses were done combining CD8 T lymphocytenumberand HLA-DMBexpressionwithstandardprognostic factors. Results: Marked CD8 T lymphocyte infiltration of the tumor epithelium is associated with a 20-month improvement in median overall survival. Additionally, when combined with cytoreduction status and age, CD8 T lymphocyte status is an independent prognostic factor for survival. Microarray analysis showed HLA-DMB, a component of the MHC II antigen presentation machinery, to be differentially expressed in specimens with an abundance of tumor-infiltrating CD8 T lymphocytes. This relationship was validated at both mRNA and protein levels. As well, high HLA-DMB expression in the tumor epithelium was associated with a significant improvement in median overall survival in both univariate and multivariate analyses. Conclusions: Tumor cell expression of HLA-DMB is associated with increased numbers of tumor-infiltrating CD8 T lymphocytes and both are associated with improved survival in advanced-stage serous ovarian cancer.

Tumor infiltrating lymphocytes in ovarian cancer

“…The presence of HLA-DMB has been associated with increased numbers of CD8C TILs and increased survival in a study of 184 ovarian cancer specimens. 20 HLA class I expression on ovarian cells is correlated with TIL infiltration and improved ability to expand TILs ex-vivo in a sample of 17 ovarian cancer patients. 74 It is notable however, that ovarian cancer cells appear prone to HLA downregulation and frequently have disabled antigen processing that may allow for immune escape and thus limit the utility of TIL therapy.…”

“…17 Similar results have been reported extensively elsewhere. [18][19][20][21][22][23][24][25][26][27][28][29][30][31] Three other studies indicate that both CD3 and CD8C TILs are of good prognosis in ovarian cancer. [32][33][34] While CD8C TILs appear to be best associated with improved survival, still other reports indicate that CD4C TILs are the subset of value in prognosticating ovarian cancer.…”

Antibodies to gp120 and PD-1 Expression on Virus-Specific CD8 + T Cells in Protection from Simian AIDS

“…Of particular importance are genes like PPP2R5C, ATF2, ATF4, PTEN, MAP3K4, MAP3K7, MAPK1, NIN, RAP1, and YWHAZ, which are known to have proapoptotic activity and to be implicated in the negative control of cell growth and division (42)(43)(44). On the other hand, genes within pathways upregulated in 2 ϫ MVA such as TAPBP, HLA-DQB1, HLA-DMB, CIITA, IRAK1, IGBP1, and CCND2 are involved in major histocompatibility complex (MHC) formation and presentation, indicating immune activation as well as cell persistence (45)(46)(47). The upregulation of genes involved in MHC class II maturation and peptide presentation were also observed independently when we analyzed the data using the ingenuity approach (Fig.…”

“…IRAK1 binds to the IL-1 type I receptor following IL-1 engagement, triggering intracellular signaling cascades leading to transcriptional upregulation and mRNA stabilization. IGBP1 is involved in the proliferation and differentiation of B cells (22), while CCND2 is essential for the control of the cell cycle (45). This upregulation of genes involved in MHC-II maturation and peptide presentation was also scored when the gene data were analyzed using the ingenuity approach (Fig.…”

Prognostic significance of B cells and pSTAT3 in patients with ovarian cancer

“…In these studies, TILs were characterized by expression of CD3 and/or CD8. [1,3,4,5,6,7,8,9,10,11] The observed correlations between T-cell infiltration and clinical outcome is a biologically plausible one -specifically, CD8…”