Memory T cells in the immunoprevention of cancer: a switch from therapeutic to prophylactic approaches

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. This review analyzes 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.

Background/introduction:

The prognosis of various cancers/neoplasms is dramatically better when the tumor is detected early (1). Similarly, the widespread usage of cancer vaccines for oncogenic viruses, such as the human papilloma virus (HPV) and hepatitis B (HBV) vaccines, has led to a decrease in the incidence of cancers caused by those viral infections (2, 3). As the incidence of cancer continues to rise (4), we need to innovate better methods for the prevention or early detection of cancer.

Preventive approaches to cancer are likely to be more effective than therapeutics. As cancer progresses and becomes more metastatic, it often gains more mutations (5) and generates a more immunosuppressive tumor microenvironment (TME). The immune system is already quite effective in combating cancer, however, through immunoediting, cancer cells can escape elimination, exhaust T cells, activate tolerogenic regulatory T (T_REG) cells, and outcompete immune cells for resources (6–9). One could potentially overcome immune escape by either increasing the frequency of certain subtypes of non-exhausted tumor-specific lymphocytes, or by altering those existing lymphocytes to be less affected by immunoedited cancer cells. Hence, the elimination of cancer/precancer cells prophylactically through increased immunosurveillance could be a viable option for cancer prevention.

Probably the greatest limitation to innovating cancer immunoprevention strategies is knowing which tumor antigens one should target, as there is no way to predict a priori who will get cancer, when, what type of cancer they will acquire, and which mutations it will harbor. However, with the revolution in cancer genetics over the past decade, catalyzed by next generation tumor sequencing, we currently have a wealth of common target mutations. Moreover, the likelihood of developing cancer in one’s lifetime is 1:2 in males and 1:3 in females (10), nearly as high as acquiring a prevalent pathogen like CMV. Therefore, it isn’t unreasonable to consider cancer vaccines in much the same way we do childhood vaccines for pathogens. To extend the analogy, while unaware of when and which pathogen a child will encounter, the likelihood that they will encounter it is exceedingly high; hence, we vaccinate against various pathogens early on in life, protecting against them with specific memory T and B cells. Likewise, the breadth of cancer predisposing events is vast; however, we are arguably entering an era in which we can consider prophylactically addressing these common features prospectively.

Cellular immunotherapies, such as dendritic cell (DC) (11, 12), tumor infiltrating lymphocyte (TIL), and chimeric antigen receptor T cell (CAR-T) therapies (13), have emerged as treatment strategies for a range of cancer types. Simultaneously, our understanding of memory T cells and their various types has increased. Memory T cells could serve as potential candidates for novel forms of cancer immunoprevention due to their extended lifespans as well as their rapid and robust responses (14). As memory T cells are functionally diverse, certain subtypes possess characteristics that could be preferable over others for the prevention of cancer. Through determining which subtypes have good memory, versatility of location, diverse methods of reactivation, and strong correlations/causations with potent antitumor responses, this review article seeks to discuss the subtypes of currently recognized memory T cells in the prevention and protection against cancer. Though discussed briefly below, the types of potential cancer vaccines have been reviewed elsewhere (15, 16).

Methods of Cancer immunoprevention:

Preventive Cancer Vaccination

Except for the few highly effective prophylactic vaccines against virally induced cancers caused by HPV and HBV, most attempts to vaccinate against non-virally induced cancers remain experimental, and are used therapeutically, after cancer diagnosis and mostly after metastasis. However, the advance in knowledge of common cancer oncogenes and inherent risk based on demographics, coupled with the identification of T cells that can recognize oncogenic mutations, makes the idea of prophylactic cancer vaccines more viable.

The possibility of prevention is often sidelined due to the perceived lack of, or perhaps surplus of targets; there being a great diversity of cancer types one could develop, and an even greater variety of antigens displayed on those cancer cells. However, there are established common mutations or neoantigens that could be vaccinated against, like KRAS G12V/G12D, BRAF V600E, IDH1 132H, etc. (17). Numerous feasible vaccination types exist to expose our immune systems to such antigens, including mRNA, viral vector, long peptide, or DNA vaccines (18). One could even ensure local immunity through prime and pull methods, where memory T cells are induced through vaccination, then pulled into tissues commonly associated with developing cancer (19).

In the pursuit of therapy, one should also take into consideration the role of bystander memory T cells (identified by a lack of CD39) (20). While not targeting tumor antigens, these cells can make “cold” tumors “hot” again following reactivation by inflammatory cytokines (21–23). Bystander T cells that have been reactivated multiple (2 to 4) times, are more sensitive to inflammatory cytokines, and hence can reactivate as prolifically as antigen-induced memory T cells (23). Likely, these bystander memory T cells could be useful in cancer prevention, especially for tumors that may have lost expression of tumor antigens, by recruiting other types of immune cells that have tumoricidal properties like macrophages and NK cells.

Preventive T-cell therapy

An alternative paradigm that has yet to receive significant consideration is that of preventive T-cell therapy (PTCT), the autologous/allogeneic administration of genetically modified T cells that recognize common tumor antigens for cancer prevention (i.e., seeding the host with an increased number of memory T cells prior to cancer onset). The principal reason for therapeutically administering genetically modified T cells is to provide patients with effector and memory T cells that can recognize tumor antigens known to be expressed by the malignant cancer cells (e.g., CD19 on B cell lymphoma) already present in the host. In contrast, the rationale for prophylactically administering cellular therapy would be to provide the cancer patients of the future with memory T cells that recognize common tumor antigens that they may begin to be expressed in cells as they become malignant. Such antigens may include common mutations (TP53, PIK3CA, RAS family), or tumor-associated antigens (typically unmutated) (e.g., cancer-testis antigens or oncofetal antigens). Preventive T-cell therapies have not been considered, partly due to the fact that it would be difficult to predict the actual epitope that could be expressed in a patient’s future tumor and fear of transferring self-reactive T cells. Additional concerns are exorbitant costs, and the need for autologous approaches to ensure human leukocyte antigen (HLA) matching for graft-versus-host disease avoidance (24). Some ways to overcome these hurdles include matching of patient HLAs with donor T cells or through the replacement of α/β TCRs with non-specific γ/δ, or HLA-independent TCRs (25–29). Alternatively, CAR T cells could be affordably generated in vivo (30–34). Given the long-lived nature of transferred T cells, it would also be important to have mechanisms to temporarily, or permanently turn off functionality to avoid any unnecessary toxicity. Indeed, self-destruct and on/off CARs are already in development (Figure 1) (35, 36).

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).

Preventive T-cell therapy could fill a niche that vaccination cannot, with the ability to embed primed, anti-cancer TCRs or CARs intraepithelially at a high density for sustained immunosurveillance. Moreover, the cellular therapeutics could be engineered for certain traits (e.g., immunosuppression resistance), and the propensity to target non-immunogenic/non-MHC restricted cancer antigens. Importantly, the cellular approach could be used in tandem with cancer vaccination strategies to provide a holistic cancer prevention strategy (37, 38).

Anti-tumor memory T cells:

Around 20 years ago, two distinct subtypes of memory T cell were identified, CCR7⁻ CD62L⁻, or CCR7⁺ CD62L⁺ cells, subsequently named the effector memory T cell (T_EM), and the central memory T cell (T_CM) respectively. The T_EM primarily circulate within the blood, whereas the T_CM can reside in lymph nodes and circulate the periphery (39). Since the original paper, several other subtypes of memory T cells, identified by function, phenotype, and location were discovered, including the stem memory T cell (T_SCM), the tissue-resident memory T cell (T_RM), and others (14, 40). Below are the defining phenotypical and functional characteristics of such cells, and their efficacies against cancer; critical when optimizing for the best form of cancer immunoprevention.

Central and Effector memory T cells

The central memory T cell (T_CM) can be identified through its high expression of CCR7 and CD62L, which allows it to circulate and reside within lymph nodes, home to secondary lymphoid organs, and cross high endothelial venules (41). These cells produce high IL-2 but lower levels of effector cytokines (42), and as a result, tend to persist and proliferate greatly in response to antigen stimulation; albeit at the cost of low immediate effector capacity (43). Effector memory T cells (T_EM) typically express no, or less CCR7/CD62L compared to T_CM (39). In general, T_EM circulate in the blood, and possess high immediate effector capacity (Perforin, IFN-γ, IL-5, and IL-4) (42).

T_EM are the most common memory T cells in various cancers, including breast and melanoma (44–47). There is a positive correlation between T_EM frequencies and survival in advanced melanoma patients receiving ipilimumab treatment. Those with high T_EM frequencies (>30%) had a median overall survival (OS) of 80 weeks, compared to 34 weeks in those with low T_EM frequencies (48). However, likely due to their regenerative potential of secondary effector cells, T_CM have more potent and proliferative responses against several murine tumor models than T_EM (49–51). T_CM are more effective against tumors and have longer persistence in the spleen, bone marrow (BM), and blood than T_EM, which had tumor progression rates analogous to control mice (52). After adoptive T cell treatment in murine models, donor cells with higher percentages of T_EM correlated with lower rates of both therapeutic efficacy and T cell expansion (53, 54). Overall, while T_EM are prevalent in varying cancer types, these cells have mixed results in terms of impact on tumor growth, and it appears that T_CM are appreciably more effective at combating tumors.

Tissue-resident memory T cells

Many tissue-resident memory T cells (T_RM) stably express CD69 (55,56), which enhances tissue retention, and CD103 (55,57), which alongside CD49a, is believed to help with tissue adherence and surveillance (55–57). Expressing these proteins allows T_RM to reside in and patrol intraepithelial spaces, acting as the niche-specific first responders to pathogens (58–61). T_RM have been identified in almost every single tissue examined (59, 62–69). In their respective niches, T_RM require different cytokines and chemokines to thrive, contributing to their tissue-specific functions (69). For example, 4–1BB and CXCR3 in the lungs, CXCR6 and CCR10 in the skin, and CCL28/CCL25 in the gut (59, 70–77).

The phenotypic characteristics of T_RM render them extremely promising candidates for immunosurveillance within niche tissues, with the unique potential to address tissue-specific cancers (78). Indeed, T_RM show great promise in fending off tumor growth, with immunosurveillance showing significant correlations with prolonged disease-free-survival, relapse-free survival, and overall survival in a broad range of solid tumors (37, 44, 47, 56, 79–96). (59,87,98). Additionally, T_RM have been shown to amplify existing circulating memory T cells responses (97). Overall, T_RM have enormous potential as tissue-specific immunosurveillers of cancers.

Stem memory T cells

Stem memory T cells (T_SCM) are CD45RO-/CD45RA⁺, and CD95⁺, yet CD31⁻, differentiating themselves from T_CM and naive T cells (T_N). Compared to T_N and T_CM, the T_SCM subset diverges in the expression of genes associated with functional differentiation, categorizing them as “highest stemness” antigen-experienced T cell (Figure 2) (98). T_SCM are found in blood and lymph nodes, potentially reactivating more effectively in lymph nodes, as they express CCR7 and CD62L (98, 99).

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 T_SCM, then T_CM, then T_EM. Phenotypes can be fluid, differentiating based on cytokine encounters. For example, T_SCM has a bias towards becoming T_CM, T_EM, or T_RM, (98, 201). T_CM has the capability of turning into T_RM or T_EM (97, 202, 203). T_RM can turn into T_CM and T_EM, being able to reconstitute blood memory as T_EM, with T_EM being capable of morphing into T_RM 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 T_EM 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 T_SCM and T_CM presence during transplantation (106).

T_SCM have superior antitumor responses, greater proliferative capabilities, more tumor infiltration, and mediate longer sustained tumor regression upon transfer than naïve T cells, T_CM, and T_EM; with differentiation status inversely correlating with antitumor capability (54, 98, 100). T_SCM expand at rates 10 times greater than T_CM, and 30 times more than T_EM post-transfer, with T_SCM exhibiting superior survival and antitumor activity (101). Robust effector cell responses were also correlated with the expansion of T_SCM in melanoma patients, potentially resulting from T_SCM differentiation into effector-type cells (102). CAR-T cell lines with high T_SCM frequencies also have a greater proliferative capacity (53, 103), and more effectively eliminate leukemia cells, initiating long-lasting antitumor effects with greater survival (104, 105). Finally, in patients treated with CAR-T, those with greater T_SCM and T_CM preservation had long-term CAR persistence. More than 2 years after CAR treatments, the contribution of T_SCM to the clonal pool in these patients was 60.5%, expanding from initial frequencies of only ~1–2% (106).

Optimal memory T cell characteristics for cancer immunoprevention:

Several considerations arise when evaluating candidate memory T cells for cancer prevention. These factors being: their longevity, plasticity of phenotype, proliferative capacity, methods of reactivation, and whether the goal is to implement localized or global protection against cancers. Arguably, the cell that excels in these factors should be considered most ideal for cancer prevention.

Clonal longevity

The consideration of clonal longevity is extremely important when it comes to cancer immunoprevention design, as one would want to create the longest-lasting immunity for the prevention of a disease that has either yet to happen or will likely reoccur. On an individual basis, most memory T cells are not long-lived. Instead, the memory of a specific antigen is passed down through the process of homeostatic proliferation. Thus, the longevity of an antigen-specific clonal “tribe” is likely more important than that of each memory cell (107).

The lifespan of memory T cells is determined by cytokine interactions (e.g., IL-15 and IL-7), their differentiation state (i.e., memory cell subtype), and the number/type of antigens it encounters over its life. In individuals vaccinated against smallpox, virus-specific T cells can last for decades, decreasing with a half-life of 8–15 years (108). In a more subtype focused study, tumor-associated T_EM and T_RM clones in patients who had melanoma persisted for 6 to 9 years in the blood and skin (109). T_RM display exceptional clonal longevity, surviving long term in the intestinal mucosa (>1 year) (110), the brain (>120 days) (111), transplanted livers (>11 years prior) (112), and the skin (10 years post hematopoietic stem cell transplantation) (113). Mechanisms contributing to T_RM persistence seem to vary by tissue type and the ability to be replenished by circulating T cells (lungs, kidneys, and liver) (112, 114). Moreover, T_RM have long-lived memory in some tissues, in contrast to shorter memories in other tissues (like the lung, >15 months allograft) (115–119). A quiescent, slow cycling T_RM subtype has also been described, hence such T_RM may have longer individual lifespans due to lower metabolic demands over time (120, 121). T_SCM, and some T_CM derived from genetically altered hematopoietic cells were able to maintain their “stemness” and persist for up to 9–12 years (122, 123). Two kinetically heterogeneous subsets of T_SCM have been reported, one long-lived and one relatively short-lived, with modelled half-lives of 9 years and 5 months (5.8% and 94.2% of the population) respectively (124). Finally, yellow-fever virus specific T_SCM-like cells were identified in individuals who received the yellow fever vaccine more than 25 years ago, while still being functionally competent ex vivo (125).

Since cells that can convey the longest immunity against cancer are the most ideal for immunoprevention, current evidence indicates that In T_SCM and T_CM might have the advantage over more differentiated subtypes. However, the longevity of T_RM should not be under appreciated and more work needs to be done to determine their lifespan in tissues in humans.

Methods of reactivation

APCs and CD28 are vital for the strong response of certain memory cells, whereas others are more promiscuous in mechanisms of reactivation. Depending on the mode of reactivation, the intensity and rapidity of responses differ. In the context of cancer, it is important to have multiple methods of reactivation, as cancer cells deter the attraction of DCs through PGE2, and have extremely low, if any CD28 expression (126, 127).

There is substantial evidence supporting the reliance of T_CM on professional APCs for reactivation; seeing as the deletion of DCs impaired T_CM reactivation significantly (~90%), leading to a failure in protection against virus challenge (128, 129). In contrast, CD62L⁻ T_EM reactivation was impacted, but not as severely as T_CM cells, when DCs were depleted. This suggests that T_CM have more reliance on DCs than T_EM (129). Although fewer studies are available for T_SCM, considering their transcriptional similarity with T_CM and T_N, which are exclusively reliant on professional APCs for reactivation, T_SCM reactivation likely depends on conventional DCs (cDCs). This probably stems from the preferred localization of T_CM and T_SCM in T cell zones of secondary lymphoid organs (129, 130).

Reactivation of T_RM differ from circulating memory T cells since the former can be activated by both professional APCs and infected cells with rapid kinetics (131–134). Notably, murine lung T_RM reactivation following influenza or LCMV re-infection was largely unaffected by DC depletion (139)Further, non-hematopoietic cells were sufficient to reactivate lung T_RM cells in influenza reinfection, showing that lung T_RM cells can acquire antigen from both immune and non-immune cells (139)T_RM also elicit anti-viral states in tissues locally by activating DCs and NK cells, while also increasing B and T cell infiltration (131), demonstrating the key role for T_RM in amplifying and broadening antitumor responses in tissues (135).

Of the cells described in this section, TRM are stand outs with regard to intraepithelial immunosurveillance and immediate response, especially because they also can be reactivated directly by cancer cells themselves. Considering that most cancers start and occur within tissues, and that many cancers have mechanisms of deterring APCs (the deterrence of DCs via PGE2) (126), active cancer immunosurveillance by T_RM with their diverse methods of reactivation could prove advantageous.

Putting cancer immunoprevention into practice:

To deploy cancer immunoprevention, certain techniques might benefit memory T cell preservation and efficacy. Additionally, one of the most vital elements to consider is the antigen that the therapy targets. Certain antigens may work well with vaccination, whereas other atypical antigens may be better for cell therapy. Taking this idea to the clinic will require an understanding of potential target antigens, and the methods of phenotypic induction for each of the memory T cell subtypes.

Types of antigens for cancer immunoprevention

Many cancers share mutations in the same genes that have key roles in suppressing the division of cells with damaged DNA (tumor suppressors), expedite the rate at which cells grow (oncogenes), or hitchhike alongside these driver mutations (passengers). Proteins synthesized from the mutated genes are often broken down and presented on the surface of MHC class 1 molecules. Some examples include mutated TP53, which is present in more than 50% of cancers, and the “undruggable” RAS, which is mutated in >30% of cancers; both of which are subject to targeting via CARs and TCRs in clinical trials (136–142). In addition, there are premalignant mutations, such as the mutant adenomatous polyposis coli gene in colorectal cancers, targeting of which could halt tumor progression at a precancerous stage (143–145). Senescent cell elimination via CAR-T cells could be an alternative approach to the prevention of cancer, as uPAR specific CAR-T cells prolong survival in mice with lung adenocarcinomas (146). Another category of targets could be cancer/testis (CT) antigens like MAGEA, NY-ESO-1, SSX2, CT83, and PRAME, due to their prevalence on early cancers, and differential expression on cancer and germline cells (147–153).

Recently, a TCR clone MC.7.G5 was identified capable of eliminating multiple cancer types (e.g., melanoma, colon, leukemia, breast, prostate, ovarian, bone, and lung cancer cells) without a common MHC peptide. Importantly, this TCR clonotype did not react with non-cancerous cells. Interestingly, CRISPR screening identified that MC.7.G5 is restricted by the monomorphic MHC I-like protein MR1, yet the MR1 ligands that MC.7.G5 recognizes to differentiate between cancerous vs non-cancerous cells are still unknown (28). This was not the first time that targeting MR1 was shown to be effective against many cancers (154). Thus, targeting MR1 and other pan-cancer molecules using preventive adoptive therapy could be HLA-agnostic, off the shelf, long-lived, and tissue specific.

Inducing various phenotypes for cancer immunoprevention

To create ideal populations of cells for the prevention of cancer, certain long-lived tumor infiltrating phenotypes should be induced in memory T cells. One could do so by engineering these cells with traits found in T_RM (tissue residence and tumor infiltration) and T_SCM (proliferative capacity and multipotency to generate effector cells).

Enhancing tissue residence and tumor infiltration

The method of vaccine administration heavily influences the phenotype of cells that one inducts, with the route of induction or transfusion also dictating tissue residency. Intranasal routes, for example, have been effective in inducing T_RM populations not only in pulmonary tissues, but also in the reproductive tract (155–167). Intramuscular, intravenous, and subcutaneous approaches can induce T_RM in tissues varying from the lungs to the liver, skin, and others (16, 64, 168–170). Using certain antibody, cytokine, nucleic acid, and small molecule adjuvants can increase T_RM numbers through DC recruitment, the activation of epithelial cells, and T_RM imprinting (64, 162, 164, 166, 171–176).

Location of cell residency is not necessarily set in stone. In skin, T_RM are capable of dispersing from the area of initial antigen encounter to other non-infected areas of skin, providing global skin immunity, and forming in the tumor-distant mucosa post vaccination (69, 177, 178). Although T_RM localization typically happens near the point of infection, the cells can be directed via a prime and pull/trap method, whereby T_RM are activated and then compelled to a certain region via an agent such as a chemokine, cognate antigen, or topical inflammatory drug (64, 167, 179–186). Directing immunity to specific tissues could be possible using “self-driving CARs”, which direct memory T cells to basal chemokines in specific tissues, such as the skin via CCR10, or the intestines via CCR9 (Figure 1) (187–189).

Enhancing proliferative capacity, longevity and multipotency

Methods of T_SCM induction via vaccination have not been well defined. Following both yellow-fever (125) and lentiviral vaccination against HCC, T_SCM were induced (190). Methods for inducing T_SCM ex-vivo; however, are well known, and include the use of certain cytokines like IL-7, IL-21, but most significantly, IL-15, which induces a T_SCM-like CCR7⁺ CD45RA⁺ phenotype that provides greater antitumor responses and enhanced self-renewal (100, 103, 104, 191, 192). Typically, naive T cells are the starting source for T_SCM, but alternative approaches have emerged, where T_EM or T_CM are induced into an “iT_SCM” phenotype via DLL1-expressing OP9 stromal cells alongside IL-7 (101, 193, 194). Another important consideration when triggering a T_SCM phenotype is the Wnt/β-catenin pathway; GSK-3ß inhibitors and Wnt3a have been shown to induce naive T cells into a T_SCM phenotype through the signaling of this pathway (98, 101).

Conclusions:

Immunoprevention could benefit at least four groups of individuals: [1] those with cancer who have gone into remission but are wary that malignancy will return, [2] those with an early detection of cancer, [3] those genetically predisposed to cancers in certain tissues, and [4] those without any malignancy or predisposal whatsoever.

For individuals in remission, memory T cells could either target prominent antigens/neoantigens present on their previous cancer, or possess a TCR from effective TILs. These memory T cells could either be tissue-specific or circulating globally in search of metastases. Those who undergo early detection, potentially via liquid biopsy, could benefit from a less invasive prevention strategy employing memory T cells specific for antigens predicted by circulating DNA (195). For the third group, T_RM could be transferred into tissues that have a genetic or hereditary predisposition to cancer, like the breast in those with a BRCA family mutation. The target antigen should be present in the cancers one prevents; for instance, those with BRCA1 mutations typically have triple-negative breast cancer (TNBC). Hence, an exemplative preventive antigen target could be α-lactalbumin, which is genetically overexpressed in ~70% of all TNBCs (152). The final group consists of those otherwise healthy, who lack a genetic predisposition to cancer. Applying immunoprevention to this category of individuals could be difficult, as uncertainty arises when determining what to target. Risk-benefit analysis would be especially important for this group, considering the lack of immediate medical need. This fourth group could utilize long-lived circulating T_SCM against targets that aren’t restricted to one type of cancer, like MR1 and those listed in the section above.

While there are several challenges to cancer immunoprevention, like the vast landscape of tumor antigens, the need to target enough antigens to prevent tumor escape, and the potential for autoimmune responses when targeting certain antigens (196), these are all currently being tackled. Strategies such as identifying shared antigens, using combination therapies, utilizing precision medicine approaches, and conducting preclinical studies all show promise, moving the potential of cancer immunoprevention closer to reality.

Memory T cells are critical for maintaining immunity against both pathogens and cancers. Over the last two decades, the discovery of memory T cell subtypes differing in function and phenotype, has elucidated key players in memory retention. This review sought to identify the ideal memory T cell subtype for cancer prevention using the criteria of clonal longevity, location, residence, activation requirements, and efficacy in cancer response. Tissue-resident memory T cells could act as the niche protectors of specific tissues, for example, if one is genetically predisposed to colorectal or breast cancer. Increasing the density of T_RM specific for those cancers in said regions could provide local immunity before a tumor can take hold. In tandem, a less differentiated memory T cell, such as the stem memory T cell, could act as a circulating bastion of cancer-fighting cells, providing whole-body immunity to cancer, potentially even targeting antigens that are not conventionally immunized against, and universally present, like MR1. Through the utilization of memory T cell subtypes that confer long-lived, intraepithelial, or whole-body immunity, one could enact robust and precise protection against a range of cancers.