How scattered tumor cells evade immune destruction?

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How scattered tumor cells evade immune destruction?

How scattered tumor cells evade immune destruction?

Scientists have unraveled the mystery of how scattered tumor cells evade immune destruction – it turns out that T cells simply can’t find them.

In 1950, physicist Enrico Fermi posed the question: If there are abundant civilizations in the Milky Way, why haven’t we detected any signs of them?

Indeed, a similar puzzle perplexes immune cells.

A small number of disseminated tumor cells (DTCs), shed from solid tumors like breast cancer, can lie dormant in the bone marrow, lungs, and other sites for 5, 10, 20 years, or even longer. When awakened, they proliferate again, causing more dangerous metastatic tumors. Despite being present and seemingly vulnerable, why do immune cells, engaged in a “interstellar patrol” within the vast universe of the human body, still fail to eliminate them?

There are various explanations for Fermi’s Paradox, and one of them is the “dark forest theory.” Addressing the immune cell conundrum, researchers led by Stanley R. Riddell and Cyrus M. Ghajar from the Fred Hutchinson Cancer Center in the United States proposed the concept of “relative scarcity,” published recently in the journal “Cancer Cell.”

Behind “relative scarcity” is a simple probability problem. To eliminate a threat, the immune system must first find it. However, in the immense “cosmos” of the human body, the number of DTCs is too small. Antigen-specific T cells, capable of destroying them, constitute only a fraction of the vast immune cell population. This mismatch means they might not have the chance to encounter each other at all!

To address this, Cyrus M. Ghajar and team presented three strategies. They demonstrated that by introducing millions of T cells capable of recognizing and killing DTCs, the immune system in breast cancer mice could effectively monitor and almost completely eradicate DTCs.

How scattered tumor cells evade immune destruction?

In patients with triple-negative breast cancer, even if the primary tumor achieved complete remission with immune checkpoint inhibitor therapy, it couldn’t stimulate a strong enough immune response to clear residual scattered tumor cells (DTCs), leading to more challenging relapses or metastatic breast cancer.

Many believed that DTCs used tricks to escape immune surveillance, such as downregulating the expression of their major histocompatibility complex class I (MHC-I), crucial molecules for the immune system’s recognition and clearance of tumor cells. This could blur the T cells’ vision, preventing them from being attacked.

Initially, Cyrus M. Ghajar and colleagues reached this conclusion using a mouse model of breast cancer. After killing the primary tumor, they observed that antigen-specific CD8+ T cells in the bone marrow maintained their effector and memory phenotypes, but the MHC-I expression in DTCs significantly decreased compared to proliferating tumor cells.

However, they soon discarded this idea.

In in vitro experiments simulating the microvascular environment, T cells were observed to be capable of effectively clearing 84%-97% of tumor cells, whether in a dormant or actively proliferating state. Alternatively, when immune-deficient mice were injected with tumor cells expressing low levels of MHC-I, followed by the transfer of antigen-specific T cells, significant clearance was observed.

At the same time, enhancing the expression of MHC-I in DTCs with low-dose IFN-γ did not increase the killing capacity of T cells.

This implies that DTCs cannot withstand T cells solely by downregulating MHC-I. While they attempt to escape immune surveillance by lowering MHC-I expression, the extent of reduction is not enough to prevent the effective recognition and killing by antigen-specific T cells, indicating that other factors are at play.

Reflecting on the process, where did things go wrong?

When testing the killing efficiency of T cells, whether in vitro culture or transferring T cells to mice, both scenarios provided more opportunities for encounters between T cells and DTCs. As the dose of transferred T cells increased, the linear distance between them shortened.

This led researchers to propose a bold hypothesis – it’s not that T cells are incapable, but they simply can’t get close enough!

Indeed, this was confirmed, and researchers termed this phenomenon “relative scarcity.” By using various strategies to increase the ratio of antigen-specific T cells to DTCs and boost their interaction frequency, effective killing was achieved.

The first strategy involved injecting T cell vaccines, stimulating an approximately 18-fold expansion of antigen-specific CD8+ T cells in breast cancer mice, clearing 53% of DTCs in the lungs.

The second strategy was T cell receptor gene-modified T cell therapy (TCR-T), where the mice’s own T cells were modified to better recognize tumor cell-specific antigens. After in vitro culture and transfer to mice, the clearance efficiency was 79%-87%.

The third strategy was chimeric antigen receptor T cell therapy (CAR-T), equipping the mice’s own T cells with new weapons for an upgrade. After in vitro culture and transfer to mice, the clearance efficiency reached 98%.

To further test clinical translational value, researchers validated these findings in a mouse model of breast cancer with high expression of human HER2. The results showed that using HER2-targeted CAR-T cells derived from trastuzumab [2] (currently in phase I clinical trial [NCT 03500991]) effectively cleared 62%-74% of DTCs in the mouse lungs.

In conclusion, according to the “relative scarcity” immune evasion mechanism revealed by Cyrus M. Ghajar and team for the first time, since reducing MHC-I expression in DTCs is not a significant hurdle for T cell killing, the focus should be on creating opportunities for encounters between antigen-specific T cells and their prey. This provides interesting insights into reducing residual DTCs and avoiding the occurrence of relapses or metastatic tumors.

However, this is just the beginning of the study. Researchers found that whether relying on TCR-T cell therapy, CAR-T cell therapy for reinforcement, or vaccines to increase the number of endogenous T cells, while expanding the power of T cells can effectively kill DTCs, it still cannot achieve 100% complete clearance, with sporadic residues remaining.

A concurrent commentary article mentioned [3] that combining Cyrus M. Ghajar’s strategies with immune therapies such as immune checkpoint inhibitors may further eradicate DTCs. Alternatively, mobilizing other immune cells, such as macrophages, dendritic cells, natural killer cells, etc., may help minimize the damage caused by DTCs.

On that note, a few months ago, a research team led by Bo Zhai from Renji Hospital, affiliated with Shanghai Jiao Tong University School of Medicine, published a groundbreaking research result in the prestigious journal “Cancer Communications.” It indicated that CAR-T cells might eliminate tiny lesions and circulating tumor cells (CTCs) after liver cancer surgery, thereby inhibiting the recurrence of liver cancer.

This direction seems worth a try!

How scattered tumor cells evade immune destruction?

References:

[1]https://www.cell.com/cancer-cell/fulltext/S1535-6108(23)00439-7

[2]Vitanza, N.A., Johnson, A.J., Wilson, A.L. et al. Locoregional infusion of HER2-specific CAR T cells in children and young adults with recurrent or refractory CNS tumors: an interim analysis. Nat Med 27, 1544–1552 (2021). https://doi.org/10.1038/s41591-021-01404-8

[3]Adam-Artigues, A., Valencia Salazar, L. E., & Aguirre-Ghiso, J. A. (2024). Immune evasion by dormant disseminated cancer cells: A Fermi paradox?. Cancer cell, 42(1), 13–15. https://doi.org/10.1016/j.ccell.2023.12.017

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