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Review
. 2021 Nov;7(11):1010-1019.
doi: 10.1016/j.trecan.2021.06.007. Epub 2021 Jul 22.

Immunity beyond cancer cells: perspective from tumor tissue

Affiliations
Review

Immunity beyond cancer cells: perspective from tumor tissue

Shengyu Gao et al. Trends Cancer. 2021 Nov.

Abstract

Investigation of cancer as a cell-level disease has led to the development of cancer cell-directed therapies including cytotoxic T lymphocyte (CTL)-based immunotherapy; yet, many patients are refractory to these modalities of cancer treatment and acquired resistance frequently occurs. Of note, cancer environment controls the manifestation of cancerous cell phenotype. Helper T (Th) cells orchestrate immune defense responses targeting cancer cells as well as the tumor microenvironment. Recent studies have shown that in addition to interferon (IFN)-γ-producing Th1 cells, interleukin (IL)-4-producing Th2 cells function as potent anticancer effectors in part by promoting tumor stroma reconfiguration and tumor tissue repair. Such Th cell-mediated tissue-level immunity may be harnessed for novel modalities of cancer environment immunotherapy.

Keywords: Th1 cell; Th2 cell; cancer cell; cancer environment; cytotoxic T lymphocyte; immunotherapy.

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Conflict of interest statement

Declaration of interests The authors have no conflict of interest to declare.

Figures

Figure 1.
Figure 1.. Tissue environment control of cancer cell phenotype
Genetic mutations occur during aging in epithelial lineage of cells that are depicted in different color. Some of the genetic alterations result in clonal cell expansion, which can be non-cancerous, in particular, for mutations compatible with normal tissue architecture characterized by ordered distribution of epithelia, the blood vessels, stromal cells, and the extracellular matrix. Clonally expanded epithelial cells that are readily unbridled by the tissue microenvironment are cancer-prone. To this end, environment change such as injury disrupts the tissue structure, and creates a tumor-promoting stroma characterized by neoangiogenesis and leukocyte infiltration. The cancerous cell phenotype can be reversed under conditions of tissue environment rectification.
Figure 2.
Figure 2.. Cytotoxic T lymphocyte-mediated cancer cell immunotherapy
Administration of immune checkpoint blockade (ICB) antibodies revives the cytolytic activities of CD8+ cytotoxic T lymphocytes against cancer cells mediated by T cell receptor (TCR) recognition of cancer cell peptide neoantigen in complex with the major histocompatibility complex class I (MHCI) molecule. CD8+ T cells engineered to express chimeric antigen receptor (CAR) can also effectively eliminate CAR antigen-expressing cancer cells. Such cancer cell-directed immunotherapy approaches are limited by primary and acquired resistance mechanisms. For instance, cancer indications with low mutation burdens are refractory to ICB, and tumors that initially responded to ICB may escape due to selection of cancer cell clones that become defective in antigen presentation. Likewise, cancer cells may lose CAR antigen, and become resistant to CAR T cells.
Figure 3.
Figure 3.. T helper cell-mediated cancer cell immunity and cancer environment immunity
In the tumor draining lymph node, CD4+ helper T (Th) cells promote CD8+ T cell priming by activating conventional type 1 dendritic (cDC1) cells through the CD40 ligand/CD40 pathway, and/or through producing interleukin-2 (IL-2) and IL-21. T follicular (Tfh) helper cells further assist B cells in the B cell follicle and induce differentiation of antibody-producing plasma cells. In the tumor tissue, Th cells manifest diverse effector phenotypes including IFN-γ-producing Th1 cells and IL-4-producing Th2 cells that exhibit mutually antagonistic functions. In type 1 immunity, Th1 cells exert anti-cancer functions through assisting cytotoxic T lymphocytes (CTLs), natural killer (NK) cells, and M1 type macrophages for cancer cell elimination. Th1 cells can also directly kill major histocompatibility complex class II (MHCII)-positive cancer cells. Th1 cell-produced IFN-γ may also act on endothelial cells to induce regression of blood vasculature, and thus represents a type of cancer environment immunity. In type 2 immunity, Th2 cells exert anti-cancer functions through effector mechanisms including eosinophil-mediated cancer cell killing and M2 macrophage-dependent nutrient deprivation. IL-4-producing Th2 cells can also mount a cancer environment-directed immune response by induce vasculature remodeling and tissue repair, causing hypoxia and starvation-triggered cancer cell death.

References

    1. Nowell PC (1976) The clonal evolution of tumor cell populations. Science 194 (4260), 23–8. - PubMed
    1. Kakiuchi N and Ogawa S (2021) Clonal expansion in non-cancer tissues. Nat Rev Cancer 21 (4), 239–256. - PubMed
    1. Zhu M et al. (2019) Somatic Mutations Increase Hepatic Clonal Fitness and Regeneration in Chronic Liver Disease. Cell 177 (3), 608–621 e12. - PMC - PubMed
    1. Oviedo NJ and Beane WS (2009) Regeneration: The origin of cancer or a possible cure? Semin Cell Dev Biol 20 (5), 557–64. - PMC - PubMed
    1. Dvorak HF (1986) Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. N Engl J Med 315 (26), 1650–9. - PubMed

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