Immune Heterogeneity Between Primary Tumors and Corresponding Metastatic Lesions and Response to Platinum Therapy in Primary Ovarian Cancer

Abstract

CD3+ and CD8+ lymphocytes are well known prognostic markers in primary ovarian cancer. In contrast, the predictive value of the immune infiltrate concerning treatment response and the involvement of immune heterogeneity between primary and metastatic lesions are poorly understood. In this study, the immune infiltrate of 49 primary tumors and 38 corresponding lesions in the omentum (n = 23) and the peritoneum (n = 15) was immunohistochemically analyzed and correlated with clinicopathological factors and platinum-sensitivity. Immune heterogeneity was observed between paired primary and metastatic lesions for all immune cell phenotypes. The stromal immune infiltrate was higher in the omental lesions than in the primary tumors, which was reflected by CD45 (p = 0.007), CD3 (p = 0.005), CD8 (p = 0.012), and PD-1 (programmed cell-death protein 1) (p = 0.013). A higher stromal infiltrate of both CD45+ and CD3+ cells in the omental lesions was associated with the detection of lymph node metastasis (CD45, p = 0.018; CD3, p = 0.037). Platinum-sensitive ovarian cancers revealed a higher intratumoral CD8+ infiltrate in the peritoneal lesions compared to the primary tumors (p = 0.045). In contrast, higher counts of stromal PD-1+ cells in the peritoneal lesions have been associated with reduced platinum-sensitivity (p = 0.045). Immune heterogeneity was associated with platinum response and might represent a selection marker for personalized therapy.

PD-1 and PD-L1 expression on TILs in peritoneal metastases compared to ovarian tumor tissues and its associations with clinical outcome

“…We thus showed for the first time that the percentages of CD8, PD-1, and PD-L1 expressing subpopulations of TILs differ in primary ovarian tumor tissues and metastatic intraperitoneal tumor implants. Our findings complement recently published data on a significantly higher number of tumor infiltrating CD8 positive as well as a lower number of PD-1 positive immune cells in metastatic compared to primary lesions 13 . Additionally, in line with several previously published studies 14 – 17 our results confirm the favorable prognosis in patients with higher levels of tumor infiltrating CD8 + T cells in ovarian cancer tissue.…”

4-1BB co-stimulation further enhances anti-PD-1-mediated reinvigoration of exhausted CD39+CD8 T cells from primary and metastatic sites of epithelial ovarian cancers

“…Some studies have focused on the differences in CD8 TILs between the primary and metastatic sites, but have only shown differences in the degree of CD8 infiltration, or in the CD8/CD3 ratio among infiltrating lymphocytes. 55 56 Due to our insufficient knowledge regarding CD8 TILs at metastatic sites, current clinical or laboratory use of immunotherapy has been based on the assumption that the immunological characteristics of exhausted CD8 TILs would be similar between the metastatic and primary sites—and that if there was a difference, the CD8 TILs in metastatic sites would be less exhausted than those in the primary sites. Notably, our present results suggested that CD39 + CD8 TILs from the metastatic sites and primary sites of ovarian cancer exhibited similar exhaustion status, although the CD39 + CD8 TILs from metastatic sites were slightly less activated than those from the primary sites.…”

Integrin α2β1 Represents a Prognostic and Predictive Biomarker in Primary Ovarian Cancer

“…Serial cryosections (5 µm) were performed. The samples were stained immunohistochemically using the avidin–biotin–peroxidase method [ 24 ]. Tissue sections were fixed either in acetone for 8 min or, for the antigens ERα and PgR, in formalin for 3 min and afterwards in a citrate buffer for 7 min at 90 °C.…”

“…In the absence of standardized cut-offs for other biomarkers, cut-offs were evaluated according to the biphasic distribution or the group size (see Table 1 ). Quantitative evaluation of CD3, CD8, and PD-1, and semiquantitative evaluation of PD-L1 was performed according to Dotzer et al [ 24 ].…”