CD74 and intratumoral immune response in breast cancer

Abstract

CD74 (invariant chain) plays a role in MHC class II antigen presentation. We assessed CD74 and MHCII expression in tumor cells, as well as CD8, CD4, and CD68 tumor infiltrating leucocyte (TIL) density by immunohistochemistry in a cohort of 492 breast cancer patients. CD74 expression was associated with poor prognostic markers including patient age, tumor grade, ER status, non-Luminal A subtypes, and with MHCII expression and higher TIL densities, particularly in the Basal-like subgroup. Univariate analysis showed a favorable prognostic effect of CD74 (Hazard ratio = 0.46, 95% CI = 0.26-0.89, p = 0.022) and for combined CD74/MHCII (Hazard ratio = 0.26, 95% CI = 0.17-0.81, p = 0.014) positive status for overall survival that was only manifested in the Basal-like subgroup. CD74 and MHCII expression is associated with patient survival in Basal-like breast cancer, and the association with TIL may reflect an effective intratumoral immune response.

Keywords: CD4; CD68; CD74; CD8; MHCII.

Figure 1. Expression of CD74 (top row) and MHCII (bottom row) in the same areas of three representative tumors as determined by immunohistochemistry

These three cases scored as CD74 strong positive / MHCII strong positive (panels A and D), CD74 weak positive/MHCII weak positive (panels B and E), and CD74 negative/MHCII negative (panels C and F) for tumor cell expression. Main images taken at 200× original magnification with insets showing detail within the image. Note that TIL staining positive for CD74 and MHCII are present in stromal and epithelial compartments of all cases but were not included in scoring.

Figure 2. Overall Survival within entire cohort (All, left column) and Basal-like subgroup (Basal-like, right column) relative to status of CD74 (panels A and B), MHCII (panels C and D), and CD74/MHCII combined (panels E and F)

Kaplan Meier plots are shown with logrank test p values and n = total number of subjects within each curve.

Figure 3. The relation between CD74 and Relapse Free Survival (RFS, top row) and Overall Survival (OS, bottom row) was analyzed in a breast cancer cohort using the kmplotter tool

RFS and OS were assessed in all cases (panels A and D), Luminal A subgroup (panels B and E), and Basal-like subgroup (panels C and F) using the Jetprobe set for CD74 (Affymetrix ID: 209619) and a cutpoint at the 75th expression quartile. Kaplan Meier plots are shown with hazard ratios (HR) and logrank test p values and n = total number of subjects within each curve.

Figure 4. Tumor infiltrating leucocyte (TIL) cell densities in entire cohort (All, top row) and Luminal A subgroup (middle row) and Basal-like subgroup (bottom row) relative to positive and negative status of CD74 (panels A, D, G), MHCII (panels B, E, H), and CD74/MHCII combined (panels C, F, I)

Bars represent means +/– standard error. Black and grey bars represent intra-epithelial and intra-stromal densities of CD8, CD4, and CD68 positive TIL respectively. NS = no significance, *p ≤ 0.05, **p ≤ 0.01, ***p ≤ 0.001, ****p ≤ 0.0001.