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Review
. 2023 Sep 15;211(6):907-916.
doi: 10.4049/jimmunol.2300049.

Memory T Cells in the Immunoprevention of Cancer: A Switch from Therapeutic to Prophylactic Approaches

Siddhesh Mittra  1   2 , Shane M Harding  2   3   4   5 , Susan M Kaech  6
Affiliations
Review

Memory T Cells in the Immunoprevention of Cancer: A Switch from Therapeutic to Prophylactic Approaches

Siddhesh Mittra et al. J Immunol. .

Abstract

Cancer immunoprevention, the engagement of the immune system to prevent cancer, is largely overshadowed by therapeutic approaches to treating cancer after detection. Vaccines or, alternatively, the utilization of genetically engineered memory T cells could be methods of engaging and creating cancer-specific T cells with superb memory, lenient activation requirements, potent antitumor cytotoxicity, tumor surveillance, and resilience against immunosuppressive factors in the tumor microenvironment. In this review we analyze memory T cell subtypes based on their potential utility in cancer immunoprevention with regard to longevity, localization, activation requirements, and efficacy in fighting cancers. A particular focus is on how both tissue-resident memory T cells and stem memory T cells could be promising subtypes for engaging in immunoprevention.

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Figures

Figure 1:
Figure 1:. Various potential memory T cell modifications to enhance antitumor efficacy.
From top left to bottom right: Allogeneic memory CAR T cells, which do not cause GVHD due to the ablation of certain HLA and TCR types (25, 197), On/Off Memory CAR T cells, which can be inactivated/activated based on encounter with a small molecule (35, 36), “Self-Driving” CAR memory T cells, which have been modified to express certain chemokine receptors (198), and “Armored” Memory T cell are more resistant to immunosuppression because they have been engineered to lack PD-1 and express cytokines or proteins that boost anti-tumor immunity, e.g., IL-2, CD40L, 4–1BBL (199, 200).
Figure 2:
Figure 2:. Plasticity in phenotype and function.
Memory T cells aren’t restricted to one phenotype from the moment they differentiate post initial antigen encounter. Subtypes could be looked at like states of differentiation, with the order of differentiation, from least to greatest being TSCM, then TCM, then TEM. Phenotypes can be fluid, differentiating based on cytokine encounters. For example, TSCM has a bias towards becoming TCM, TEM, or TRM, (98, 201). TCM has the capability of turning into TRM or TEM (97, 202, 203). TRM can turn into TCM and TEM, being able to reconstitute blood memory as TEM, with TEM being capable of morphing into TRM as well (112, 114, 121, 177, 203). This paints a very interesting picture, with memory T cells morphing in phenotype when the time arises, not necessarily restricted to one subtype or another. The induction of highly differentiated cells may not be the most ideal for cancer immunoprevention, as it has been detailed that patients with a mainly TEM phenotype of CAR T cell 30 days post-treatment had their CAR presence disappear 2–4 months after, whereas greater endurance was acquired in factions with high TSCM and TCM presence during transplantation (106).
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