The immune system's monitoring of cancer itself can induce metabolic adaptations in early tumor cells

A study by the Ludwig Cancer Institute found that the immune system's monitoring of cancer itself can induce metabolic adaptations in early-stage tumor cells, while promoting their growth and enabling them to suppress deadly immune responses
.

The study, led by Ping-Chih Ho, an associate member of Ludwig Lausanne and published in the journal Cell Metabolism, details the precise mechanism by which "immune metabolic editing" occurs in emergency tumors in a mouse model of skin cancer melanoma and identifies a novel biochemical signaling cascade and proteins
that coordinate their actions.
In addition to elucidating previously unknown dimensions of tumor evolution, these findings offer important promise
for improving the efficacy of cancer immunotherapy.

"We have identified dozens of metabolic enzymes
that help melanoma immunity evademia," Ho said.
"These enzymes, along with some individual components of the signaling pathways we have identified, represent a rich potential drug target that can disrupt defenses established by immune metabolic editing
.
" These drugs, which may make tumors more susceptible to immune clearance, can also be used in combination with checkpoint blockades and other immunotherapies to overcome resistance to this type of treatment in most
cancers.
”

The immune system's monitoring of cancer is thought to promote the occurrence of malignant tumors by promoting the evolution of cancer cells, which can disrupt the detection and attack mechanisms
of the immune system.
The "immuno-editing" theory — best famously proposed by the late Lloyd Old and Ludwig's current scientific advisory board member Robert Schreiber, former scientific director and CEO of the Ludwig Cancer Institute—is now a fundamental principle
of tumor immunology.

Researchers have long known that cancer cells' common metabolic adaptations — such as their heavy consumption of glucose — disrupt the anti-tumor immune response
.
However, it is unclear whether immune surveillance can also induce metabolic adaptations in cancer cells, and whether these adaptations also help them resist immune responses
.
This is what the current study builds, revealing an aspect of tumor evolution that has been hypothesized but has so far remained unproven
.

Ho and his colleagues identified three key proteins that coordinate this effect: IFNγ, STAT3, and c-Myc
.
IFNγ is an anti-cancer surveillance tool secreted by T cells and other immune cells that is known to stop the growth
of cancer cells.
But the signals it triggers, mediated by a protein called STAT1, also induce cancer cells to adapt, helping them evade attack by T cells, a process known as immune editing
.

In their current study, the researchers show that IFNγ also activates a unique, rarely explored signaling pathway, mediated
by a related protein called STAT3.
This pathway alters the expression patterns
of cancer cell genomes by inducing "epigenetic" changes that determine which genes are active.
It also overactivates a major regulator of cellular metabolism called c-Myc, which is overexpressed
in many cancers.

The researchers showed that genes activated by c-Myc not only affect cancer metabolism, but also disrupt T cell infiltration into tumors and make them unable to attack cancer cells
.
In fact, the signaling pathways mediated by STAT1 and STAT3 appear to synergistically confer on sudden tumors the critical ability to avoid immune clearance, promote immune metabolic editing, and help them evolve into mature malignancies
.

"Previous studies have shown that loss of STAT3 activity in cancer cells promotes immune infiltration and induces tumor regression
," Ho said.
"Our findings explain why targeting STAT3 with drugs can restore sensitivity to IFNγ in cancer cells that have evolved beyond
the range of inhibition.
"

The researchers also used CRISPR genome editing technology to screen 2,078 metabolic enzymes in mouse tumors and identified 40 metabolic genes controlled by c-Myc that play an important role
in helping cancer cells evade immune surveillance and attack.
These enzymes are also prime candidates for drug targeting
.

"In addition to its pharmacological significance," Ho said, "this study sheds light on a previously underappreciated dimension of immune editing that will impact our understanding of
the metabolic dialogue between cancer cells and immune cells in the tumor microenvironment.
" ”