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J Cancer Metastasis Treat 2020;6:5 I http://dx.doi.org/10.20517/2394-4722.2020.13 Page 5 of 38

remain undefined. Ferroptosis is a recently discovered form of cell death and results from iron-dependent
accumulation of lipid peroxides. It is unclear whether, and how, ferroptosis is involved in T cell immunity,
cancer immunotherapy, and radiotherapy efficacy.

Experimental procedure: To understand the importance of ferroptosis in immunotherapy and radiotherapy
efficacy, we used genetic deletion of key ferroptosis effector genes and pharmacologic agonists and
antagonists. Lipid oxidation was quantified using C11-BODIPY. A wide variety of in vivo and ex vivo
analyses was performed in tumor and immune cells.

Results: We show that immunotherapy-activated CD8+ T cells and radiotherapy enhance ferroptosis-
specific lipid peroxidation in tumor cells, and that increased ferroptosis contributes to the anti-tumor
efficacy of immunotherapy and radiotherapy. Mechanistically, interferon gamma (IFNγ) released from
CD8+ T cells downregulates the expression of SLC7A11, a subunit of the glutamate-cystine antiporter
system xc-, impairs the uptake of cystine by tumor cells, and, as a consequence, promotes tumor cell lipid
peroxidation and ferroptosis.

Conclusion: This work establishes a novel mechanism through which CD8+ T cells function. This work
expands our understanding of the interactions between immunotherapy and radiotherapy.

6. Polyploidy and the origin of human tumors

Jinsong Liu

The University of Texas, MD Anderson Cancer Center, Houston, TX 77030, USA.

Polyploid giant cancer cells (PGCCs) have long been observed in cancer and were thought originally to
be nondividing. Surprisingly, the formation of blastomere by cleavage division after the formation of the
zygote, with progressive decrease in cell size and increase in nuclear to cytoplasmic ratio, is the first step
in embryogenesis, also shows abundant polyploidy. The evidence from our laboratories demonstrated
that the stress-induced PGCCs can divide by endoreplication (endocycle and endomitosis), which
leads to increased nuclear to cytoplasmic ratio, in turn leading to dedifferentiation of somatic cells and
acquisition of embryonic stemness. Therefore, formation of PGCCs in somatic cells may represent a
previously overlooked endogenous embryonic program that can be activated to dedifferentiate somatic
cells into stem cells of various potencies for tumor initiation. Based on these data, I propose that human
tumors originate from stem cells at a specific developmental hierarchy, which can be achieved by dualistic
origin: dedifferentiation of the zygote (sexual) via the blastomeric-mediated cleavage division during
normal development or transformation from damaged or aged mature somatic cells via a blastomeric-
like embryonic program (asexual) via formation of PGCCs. Initiation of the tumor begins with stem
cells that have uncoupled the differentiation from the proliferation program, which results in stem cell
maturation arrest. Thus, the birth of a tumor can be viewed as a triad that originates from stem cells via
dedifferentiation through a blastomeric or blastomeric-like program, differentiation along Waddington’s
landscape, and arrested at a specific developmental hierarchy. The significance of polyploid blastomere-like
cancer stem cells in cancer therapy is discussed.

7. Ketogenic diet as a cancer treatment: in vitro quantification

Edward Henry Mathews, George Edward Mathews, Albertus Abram Meyer

CRCED, North West University, Silver Lakes 0054, South Africa.