Aiming to immune elimination of ovarian cancer stem cells

Figure 1 Survival of patients diagnosed with ovarian carcinoma. The percentage of survival after diagnosis is not significantly increased in the past 20 yr (Source from Integraal Kanker Centrum, The Netherlands) .

Figure 2 Killing the mature cancer cells leaves the root intact leading to regrowth of the tumor. Killing the root will exhaust the stem cell pool leading to eradication of the tumor. Reprinted from Jones et al[154].

Figure 3 Hypothesis of specific targeting of primitive cancer stem cells. In a non-immunosuppressive tumor microenvironment, Oct4-specific T cells (αOct4 T cell) can recognize the primitive cancer stem cells (CSCs). and destroy them. Progenitor cells (Pro) differentiate to more mature tumor cells and will eventually undergo apoptosis or necrosis. Once some progenitors regain the self-renewal machinery and re-express Oct4 to become a CSC, T cells will also eliminate it. In this way, the tumor loses its ability to generate new tumor cells.

Figure 4 Immune-suppressive pathways in ovarian cancer. Tregs are attracted to the tumor environment by CCL22, secreted by the tumor. The tumor microenvironment expresses molecules that can convert functional antigen presenting cells (APCs) into dysfunctional ones. These dysfunctional APCs in turn stimulate Treg differentiation and expansion. pDCs are also present in the tumor environment and stimulate tumor growth by releasing tumor necrosis factor-α and interleukin-8. (modified from[132]). pDCs also facilitate immunosuppressive function of FoxP3⁺ICOS⁺Treg[123].

Figure 5 Dysfunctional immune system in peritoneal cavity of patients with ovarian cancer. Many types of immune cells are recruited to the ovarian tumor site, including regulatory T cells (Treg), dendritic cells (DC), tissue associated macrophages (TAM) myeloid derived suppressor cells (MDSC)[155], plasmacytoid DCs (pDC), natural killer cells and T cells (CD4, CD8). Once being recruited, most cells function abnormally and become immune suppressive. T cells specific for Oct4 (αOct4 T cell), CD4⁺ T cells, CD8⁺ T cells are damaged, due to dysfunctional DCs, pDCs and suppressive Tregs. Also the secretion of immune suppressive cytokines and lipid metabolites contribute to establish such an immunosuppressive tumor microenvironment, and may also be required for cancer stem cells (CSCs) maintenance. So even if the CSC is recognized, T cells lack the ability to eliminate it. Whereas such suppression mechanisms are not operative in the peripheral blood of the patients, once the CSC migrates to the peripheral, it is killed.

Figure 6 PD-1 and Tim-3 expression by ascitic lymphocytes from patients with ovarian cancer. PD-1 expression was undetectable in ascitic lymphocytes. Compare to isotype control, peripheral blood lymphocyte (PBL) from healthy express 2% Tim-3, ascitic CD4⁺ and CD8⁺ cells express four times more Tim-3 than control PBL.