Lymphopenia is a marker of more severe SARS-CoV-2-induced diseases. Extreme T-cell activity within the lungs causes hyperinflammation. NLR measurement is of prognostic value in patients with active SARS-CoV-2.

Efficacy of immunotherapy relies partly on CD8⁺ T-cell trafficking into the tumor area (40). Infiltration of CD8⁺ T cells is low in advanced cold cancers, which is a reason for low or no immunotherapy response from such type of cancer (12). Colorectal cancer (CRC), for instance, shows lower CD8⁺ T-cell density in advanced vs. early stages (40). In patients with advanced pancreatic cancer, low infiltration of CD8⁺ T cells and high expression of programmed death ligand-1 (PD-L1) are associated with high number of cancer stem cells (CSCs), which show immunosuppressive effects (41). In addition, presence of CD8⁺ T cells is also considered as a prognostic marker in breast cancer (42), which is associated with reduced risk of death from the disease (43). By contrast, T-cell infiltration is higher in hot cancers, thereby representing better response to ICI therapy (40). The fraction of cytotoxic T cells (CTLs) is different in three categories of tumor patients. Based on outcomes of a quite recent study, patients in the “inflamed” group represented intraepithelial CTLs of >500 cells/mm², whereas cases in the “immune desert” group had a stromal CTL fraction of ≤50 cells/mm². Patients who are not included in this cutoff range were placed in the category of the “immune excluded” group, showing a quite low number of intraepithelial CTLs (44).

Cancer-associated fibroblasts (CAFs) are the dominant cells of the tumor microenvironment (TME) that take multifaceted roles for promoting tumor aggression and metastasis (45). CAFs suppress the intra-tumoral migration of CD8⁺ T cells (46) and exclude their contact with cancer cells. This is mediated through release of C–X–C chemokine ligand 12 (CXCL12), as well as promoting extracellular matrix (ECM) stiffness (45). High activity of CAFs within the edge or invasive front of cancer and their exposure to the hypoxic conditions in this tumor region is a reason for the cold immunity of this area. CD8⁺ T cells are immunologically ignored in the edge area. The cells are induced by macrophage type 1 (M1) cells to recruit into the core area of tumor, rendering higher sensitivity of this tumor region to therapy (47). M1 cells are called classically activated cells. The cells represent a pro-inflammatory signature and have antitumor activities (48). CD8⁺ T cells possibly have a negative cross talk with myeloid-derived suppressor cells (MDSCs) in which a fall in the number of MDSCs infers a rise in the fraction of CD8⁺ T cells (49).

CD8⁺ T cells, dendritic cells (DCs), and natural killer (NK) cells form a net of functional circuity. The activity of NK cells is induced by CD8⁺ T cells. Such functional circuity will lead to a co-operative activity, maximizing effector functions of these critical cells against cancer (50). CD8⁺ T cells form CTLs upon exposure to the antigen-presenting cells (APCs), such as DCs. CTLs recognize major histocompatibility complex-1 (MHC-1)-bounded antigens expressed on target cells (17). Naïve CD8⁺ T cells will become activated when they are under exposure to the mature DCs (51) (Figure 1).

High expressions of NKG2A and NKG2D are representative of the respective CD8⁺ T-cell exhaustion and functional memory features. IL-33 is a tumor suppressor, but its upregulation in lung epithelial cells is contributed to the hyperinflammation in patients with severe SARS-CoV-2.

Successful immunotherapy relies on recovering antigen-specific effector memory T cells within the TME (74). Memory CD8⁺ T cells are important for promoting sustained immunity against cancer (75). Central memory, effector memory, resident memory, and stem-like memory cells are different subsets in this category. Resident memory T cells are placed in local tissue areas and contribute to the immediate response to secondary infection, whereas central memory and effector memory T cells circulate within blood, and their target organs are secondary lymphoid tissues (76).

Memory T cells are considered as a hallmark of antiviral immunity (77). The cells are presented in convalescent individuals from SARS-CoV-2-induced diseases (78) and are generated as a response to vaccination, infection, or after viral reexposure (8). Memory T cells are important for quick responses against infection, and their presence is a reason for the low severe condition experienced by patients upon viral reentry (21, 79). During recovery from SARS-CoV-2-induced diseases, dysfunctional T cells are converted into functional CD8⁺ memory T cells (61). Bert and colleagues evaluated T-cell responses in patients that recovered from SARS, the disease related to the SARS-CoV infection. They noticed the presence of memory T cells reactive to the SARS-CoV N protein 17 years after the SARS outbreak in 2003 (80). The dynamic transition between effector and memory T cells is also reported in SARS-CoV-2-specific CD8⁺ T cells (81). Such CD8⁺ memory T cells will reach a peak at about 2 weeks after infection with this virus. The cells are also detectable even after 100 days (8), and their response against SARS-CoV-2 is maintained for 10 months. The cells are able to form stem-like memory cells (82), but their fraction is reduced over time (8) (Figures 4, 5).

CD8⁺ memory T cells provide protection against viral reentry, but their fraction is reduced over time.

T-cell memory in cancer and cancer immunotherapy relies on the formation of antigen-specific stem-like progenitor cells (83). Stem-like T cells are T-cell factor (TCF)-1^high memory cells that represent higher proliferative capacity and produce a larger number of effector cells, as compared with other T-cell memory subsets (76). Stem-like memory T cells are multi-potent and have self-renewal potential (84). The activity of stem-like CD8⁺ T cells contributes to the complete regression of tumor and tumor-infiltrating lymphocyte (TIL) persistence in patients receiving ACT (85). Two subtypes of stem-like progenitor memory of CD8⁺ T cells are identified: progenitor cells committed to functional lineage that lack the T-cell immunoreceptor with Ig and ITIM (TIGIT) and programmed death 1 receptor (PD-1), and those committed to dysfunctional lineages that express PD-1 and TIGIT and represent exhausted-like T cells (83). Functional stem-like CD8⁺ T cells are negative for CD39 and CD69 (85) but highly express CD28 and TCF1 and are characterized as TIM-3^-CD28⁺TCF1⁺ cells (86). Such cells are dependent on TCF1 for recalling their self-renewal potential (87). TCF1⁺PD-1⁺CD8⁺ T cells share features of central memory T cells but do not represent an effector signature (88). In fact, progenitor T cells with TCF1⁺PD-1⁺ signature are referred to as memory-like cells, whereas cells with a TCF1^-PD-1⁺ expression profile are referred to as exhausted cells (87). The identity of the memory CD8⁺ T-cell pool is important from the therapeutic standpoint. Is this send a message to use ICI therapy for reinstating functional stem-like cells in immune niches? Stem-like TCF1⁺PD-1⁺CD8⁺ T cells are able to form differentiated T cells (TCF1^-PD-1⁺CD8⁺) as a response to ICI, and their contribution is vital for controlling cancer upon ICI treatment. Therefore, a proliferative response in CD8⁺ T-cell progeny is occurring in patients receiving ICI (89).

Generally, T cells will lose their effector function and promote terminally differentiated exhausted phenotype when they are under exposure to chronic infections or are encountered to the immunosuppressive milieu of TME (88, 90, 91). TCF1⁺PD-1⁺CD8⁺ T cells contribute to sustained immunity in patients with chronic viral infection (88), such as SARS-CoV-2-induced disease (84). Stem-like CD8⁺ memory T cells exist in convalescent SARS-CoV-2 individuals, and their presence is possibly indicative of long-term protection against the virus (79). Based on findings from a study, stem-like memory T cells are successfully generated in convalescent individuals, which reached a peak at about 120 days post-symptom onset (84). This is indicative of the importance of these cells in patient recovery from SARS-CoV-2-induced diseases (Figures 4, 5).

The activity of stem-like CD8⁺ T cells is contributed to the complete regression of tumor and long-term protection against SARS-CoV-2.

Hyperactivation or exhaustion is a dominate immune response in severe SARS-CoV-2-induced diseases (67). Exhaustion is a term used for progressive weakness in cytokine generation and cytotoxicity. CD8⁺ T cells are turned into an exhausted state upon chronic exposure with cancer antigens, viral infection, or in the context of autoimmune disease. The activity of these cells in chronic inflammatory conditions is inefficient, and they are not able to clear the infection (90). Thus, exhausted T cells are epigenetically distinct from memory and effector T cells through displaying defective functionality. Exhaustion is, in fact, a differentiation process that eventually causes cell death (17). CD8⁺ T cells sustain the state of exhaustion even after resolution of viral infection. Such exhausted cells show lower clonal expansion and lower encoding for molecules related to the cytotoxicity but higher rates of genes responsive to type 1 interferon (92). Kusnadi and colleagues in a study evaluated the nature of virus-reactive CD8⁺ T cells in single-cell transcriptomes of patients with a SARS-CoV-2-induced disease. Exhausted SARS-CoV-2-reactive cells showed higher frequency and represented lower inflammatory and cytotoxicity features in patients with a mild disease. By contrast, in patients with a severe disease SARS-CoV-2-reactive cells in the dominant non-exhausted subtype showed a feature of CD8⁺ T-cell memory cells, represented by enrichment with transcripts related to the antiapoptotic, pro-survival, and co-stimulation. Such cells displayed different characteristics with that for cells reactive to influenza, which is indicative of diverse functional features and transcriptome profiling for CD8⁺ T cells upon exposure to the various types of viruses (93). PD-1⁻CTLA-4⁻TIGIT⁻ CD8⁺ T cells is a non-exhausted subset that shows reduced frequency in severe diseases. Inhibition of PD-1, CTLA-4, and TIGIT is an effective way for maintaining the antiviral activity of CD8⁺ T cells (94).

Anergy is a state of impaired or hypo-reactivity (95) that is occurring in cells under suboptimal stimulation (96). T-cell anergy occurs in tumors (96) and is referred to both CD4⁺ and CD8⁺ T cells (97). Anergy is different from exhaustion and senescence. Anergy occurs during T-cell priming, whereas T-cell exhaustion occurs in cells with prior effector function but becomes silenced gradually due to the continuous presentation of antigens. Senescence is a state of growth arrest in a cell undertaking extensive proliferation due to repeated stimulation (98). Senescent T cells are terminally differentiated and represent telomerase shortening and irreversible (or stable) cell-cycle arrest (96). Thus, although both senescent and exhaustive T cells are under continuous stimulation, the latter cell type can retain its functionality under exposure to appropriate stimuli (99, 100). Exhausted T cells display elevated inhibitory checkpoints, such as PD-1 and TIM-3, which do not occur in senescent T cells. A distinct phenotype is seen in senescent cells in which the cells show downregulation of co-stimulatory molecules including CD27 and CD28 but highly express markers like CD57 (101, 102).

T cells may turn into anergic state upon exposure to an immunosuppressive TME (97). Tumor-specific T cells show dysfunction due to exposure to several inhibitory signals from the complex TME (96). TME is represented by insufficient nutrient provision for immune cells. CD8⁺ T cells take an optimal function when they are under exposure to a normal high-glucose content, whereas the cells upon exposure to a hypoglycemic milieu will transit into energy and finally undergo apoptosis (103). DC immaturity, weak co-stimulation, and/or the activity of inhibitory signals are factors related to the insufficient or suboptimal presentation of tumor antigens on T cells (97). The immunosuppressive TME presents high number and activity of Tregs. Tregs prime DCs to induce anergy in conventional T cells. This is mediated in a CTLA-4-dependent manner in which the constitutive expression of this checkpoint on Tregs results in trans-endocytosis of B7 ligands on DCs. This is followed by degradation of such ligands, which interferes with the CD28 co-stimulatory capacity of DCs (104). Thus, immature DCs in TME are not able to provide optimal T-cell activation due to lacking ligands for engaging with CD28 (105).

T-cell anergy is also considered as a hallmark of SARS-CoV-2-induced disease and is correlated with severity of the condition (95). Results of a study showed more pronounced hyporeactive T cells in hospitalized patients with a SARS-CoV-2-induced disease, and such severe hyporeactive T cells are correlated with prolonged viral persistence. SARS-CoV-2-mediated T cell hypoactivity is independent on the activity of immunosuppressive drugs administered to such patients. Such hyporeactive cells were generated due to extrinsic T-cell factors and were due to plasma components, and they were partially recovered by IL-2 (106). Hopefully, anergic T cells can be reversed after recovery from critically ill SARS-CoV-2 induced diseases.

Exposure to IL-2 partially recovered hyporeactive T cells induced by SARS-CoV-2 (95, 106) and cancer. PD-1 promotes anergy in CD8⁺ T cells through hampering the autocrine production of IL-2 from the cells. IL-2 re-complementation, by contrast, recovers the activity of anergic T cells irrespective of PD-1 expression on the cells (107). IL-2 inhibits anergic T cells through induction of JAK and mTOR and mediates its effects through suppressing the expression of genes related to anergy induction including Cbl-b and Ikaros (108). There are also transcription factors, such as nuclear factor of activated T cells (NFAT) and Egr2/3 related to the clonal T-cell anergy (109). NFAT is an important regulator of T-cell activation; its activity is related to the induction of a hyporesponsive cellular state (exhaustion or anergy) in both CD4⁺ and CD8⁺ T cells (110). Egr2 induces Ndrg1, which is kept at high levels in anergic T cells at resting state. Ndrg1 is, thus, a factor related to the clonal T cell anergy where its degradation is induced by IL-2 treatment (109).

T-cell senescence occurs in patients with chronic viral infections, autoimmune disorders, and cancer (101, 111). Malignant tumors induce T-cell senescence in order to evade from immune surveillance (101). Senescent T cells are also contributed to the pathogenesis of SARS-CoV-2-induced diseases (112). Severe infection with SARS-CoV-2 mimics a senescence immune state. The proportion of senescent CD8⁺ T cells is higher in patients with severe (vs. mild) disease. Such senescent cells are not able to produce cytotoxic molecules. Instead, they are equipped with senescence-associated secretory phenotype (SASP). SASP is a term used for a broad spectrum of molecules secreted by senescent cells, which might be a promoter of cytokine storm in patients with severe SARS-CoV-2 induced disease (111). Immunosenescence augments susceptibility to SARS-CoV-2 and blunts the efficacy of vaccination. Senescent immune cells are higher in aged individuals, which is related to the retarded immunity to vaccination therapy among elderly populations (113). Younger cases with chronic viral infection also show senescent CD8⁺ T cells (102) (Figure 5).

T-cell exhaustion, anergy, and senescence are occurring in severe SARS-CoV-2-induced diseases and cancer.

Bystander T cells are not pathogen specific, but they are able to impact the course of immune responses (114). The cells are CD39^- CD8⁺ (115), and their activation is independent on TCR signaling, rather than occurring in the context of autoimmune diseases, infection, and cancer. Such TCR-independent T-cell activation is seen mainly in CD8⁺ T cells (65). The quality of T cells infiltrated into different types of human cancers have recently been described. Bystander CD8⁺ T cells show high fractions in patients with non-melanoma cancers, such as ovarian and renal cancers (116). Bystander-activated CD8⁺ T cells release cytokines, such as IFN-γ that support immune defenses against infection. Cytokine release from activated bystander cells occurs even when the cells are not stimulated by antigens. Thus, due to not being specific, the cytolytic activity of these cells may cause host tissue damage (114, 117). For instance, in non-small cell lung cancer (NSCLC) patients under treatment with immunotherapy, a high fraction of bystander cells within the lungs can impair immune responses and enhance the rate of toxicities (118). Early responses from bystander CD8⁺ T cells are seen in cases with mild or asymptomatic SARS-CoV-2-induced disease. Such cases show no signs of systemic inflammation. This is comparable with delayed bystander CD8⁺ T-cell responses and vigorous systemic inflammation in patients with severe disease (119).

Early response from bystander CD8⁺ T cells is protective against SARS-CoV-2-induced diseases, while their high fractions impair immune responses in cancer patients.

Immunological competence is higher in antiviral CD8⁺ T cells compared with antitumoral CD8⁺ T cells.

Reduction of active CD8⁺ T cells shortly after convalescent plasma transfusion from patients with severe SARS-CoV-2 induced disease is indicative of the weakness of this approach for proving protection on other individuals.

SARS-CoV-2 vaccines act for recovering CD8⁺ T-cell responses.

PD(L)-1 blockade is presumably safe in cancer patients with SARS-CoV-2, and its application is beneficial for reducing the risk of attack from the virus.

Most cancers are evolved in patients with ages over 60, the age range estimated to dominate more than 20% of the world’s society by year 2050, which is alarming as an economic burden related to healthcare provision (147). Outcomes of a recent systematic review showed more pronounced survival benefits related to the PD(L)-1 blockade among cancer patients aged <75 compared with cases ≥75 (148). The efficacy of the SARS-CoV-2 vaccination is also noticeably diminished with age, which is due presumably to a decline in responses from innate and adaptive immunity as a result of aging (149). CD8⁺ T cells are less frequent in aged HNSCC patients, and a high expression of PD-1 on peripheral T cells is reported in such population (150). Studies showed that CD8⁺ T cells are less frequent in SARS-CoV-2 patients aged >45 compared with cases with ages <45 (24), and that the cells are not detectable in patients over 80 (28). Besides, the basal pro-inflammatory state is higher in older individuals. These along with the diminished capability for mounting appropriate immune responses are reasons for the higher severity of condition in aged SARS-CoV-2 patients (151). Aging also causes higher accumulation of senescent immune cells (152), which is a reason for higher baseline inflammation in such populations (113) and their more vulnerability to SARS-CoV-2-induced diseases (152).

Obesity is an established risk factor of cancer development, which represents a global rise and poses a high cost over public health (153). Obesity is among preexisting conditions that cause patients to be prone to a more severe SARS-CoV-2 disease (154). A possibility of experiencing a severe disease is twice in obese individuals compared with normal-weight SARS-CoV-2 patients (155). Obesity alters the balance between innate and adaptive immunity. It links with a state of low-grade chronic inflammation (154). Chronic inflammation related to obesity alters immune functionality. The number of dysfunctional CD8⁺ T cells is increased with obesity (156). T-cell exhaustion is induced by cellular interactions occurring within adipose tissue (157). Generally, diets interfering with metabolic pathways are linked positively to the increased risk of carcinogenesis (158). CD8⁺ T cells show alterations in metabolic fitness in obese individuals. Such altered metabolic activity influences differentiation and effector activity of CD8⁺ T cells and their transition into memory cells (159). Impaired activity of CD8⁺ T cells also occurs in obese patients with SARS-CoV-2-induced disease, which is indicative of a more severe condition in such cases (156). A mechanism by which obesity contributes to the increased risk of tumorigenesis is by promoting constant upregulation of PD-1 on CD8⁺ T cells and their further dysfunction (160). Transition from PD-1^–non-exhausted CD8⁺ T cells into PD-1⁺-exhausted CD8⁺ T cells is reported in breast cancer mice receiving high-fat diet (161). Taken together, it could be asserted that aging and obesity are key risk factors of cancer development, and aged or obese patients experience more severe disease upon exposure to SARS-CoV-2 due partly to the attenuated CD8⁺ T-cell activity (Figure 6).

CD8⁺ T cells are less frequent with aging, and their activity is diminished in obese individuals.

Chronic inflammation is a major risk factor of cancer. Conditions like chronic inflammation and autoimmunity account for about 15%–20% of all types of cancers. An organ with long-lasting inflammation is more prone to tumor development (162). Examples are numerous in this context, such as chronic obstructive pulmonary disease (COPD) (163), inflammatory bowel disease (IBD) (164), cirrhosis (165, 166), and chronic pancreatitis (167), which are the basis for the development of lung cancer, colorectal cancer, hepatocellular carcinoma (HCC), and pancreatic cancer. In regard to HCC, inflammatory-related events can cause chronic liver fibrosis and further chronic damages in this organ (168). A possible reason for an increase in the risk of tumorigenesis is the interrelation between chronic inflammation and chronic oxidative stress (17, 169) and the resulting impaired immune functionality and further tissue dysfunction (170). This is indicative of the virtue of using antioxidants, such as melatonin for modifying inflammatory and oxidative events in favor of immune activation against chronic injuries and cancer (171).

Chronic inflammation causes abnormal cytokine production (172), and patients with chronic inflammatory-related diseases are more prone to the SARS-CoV-2 infection. Diabetes, for instance, is a chronic inflammatory disease that affects cellular proliferation, differentiation, and function of innate and adaptive immunity (173). CD8⁺ T cells undergo exhaustion in the chronic inflammatory setting. CD8⁺ T cells served to trigger potent responses against viral infections for resolving infection. However, chronic infection is established when viruses are able to overcome this control. In fact, CD8⁺ T-cell exhaustion occurring in such conditions is a result of their constant responses to the long-lasting viral replication and the resulting continuous antigen stimulation (174). Chronic antigen stimulation drives CD8⁺ T-cell exhaustion, which further reduces their secretory cytokines. Finally, the cells undergo progressive loss of functionality (175) and apoptosis (174).

Hypoxia is another factor that is linked with tumorigenesis, tumor progression, and SARS-CoV-2 pathogenesis. Hypoxic areas are common in patients with solid tumors, which is due partly to the abnormal tumor vessels (176, 177). Hypoxia is induced by SARS-CoV-2 (178). It occurs as a response to severe respiratory dysfunction, which causes a discrepancy between uptake and consumption of O₂ (179). HIFs are by-products of hypoxia that are stimulated within inflammatory tissues. There is a positive link between acute systemic hypoxia with mortality from severe SARS-CoV-2-induced diseases. SARS-CoV-2 promotes cytokine storm, particularly in the lung environment. HIF-1α functions as an inflammatory stimulant, mediated through provoking the transition of preexisting cytokine storm into a fulminant condition (178). Low O₂ reduces antiviral responses from CD8⁺ T cells (180). Hypoxia reduces T-cell effector function through increasing the expression of co-inhibitors on CD8⁺ T cells (176). Hypoxic tumors generally show a lower fraction of CD8⁺ T cells. CD8⁺ T cells either avoid hypoxic regions or show reduced ability to expand in such areas (181, 182). Hypoxic tensions mainly influence antigen-experienced CD8⁺ T cells, namely, memory and effector cells (not naïve CD8⁺ T cells) (182). Exposure of exhaustive CD8⁺ T cells to hypoxic conditions will promote a terminal exhaustive state in such cells that are unable to recover their effector function after ICI therapy (183). Hypoxia induces the generation of reactive oxygen species (ROS) in T cells of patients with progressive (severe/critical) SARS-CoV-2-induced diseases, as compared with cases that recovered from critical diseases. High ROS accumulation and defective T-cell mitochondria are associated with severe SARS-CoV-2 diseases (184) (Figure 6).

Areas of chronic inflammation and hypoxia favor more dysfunctional CD8⁺ T cells in patients with SARS-CoV-2 induced diseases and cancer.

SARS-CoV-2 in relation to hypoxia promotes vascular abnormality (a leaky architecture) (185). A leaky vasculature is also a common feature of cold cancers. The vascular endothelial growth factor (VEGF, also called VEGF-A) is a cytokine that vitally contributes to angiogenesis (186). The rate of VEGF expression is considerably higher in patients with SARS-CoV-2-induced disease compared with healthy individuals (187). High activity of VEGF promotes vascular permeability (186). Administration of the VEGF inhibitor bevacizumab in patients with severe SARS-CoV-2-induced disease significantly improved the PaO₂/FiO₂ ratio and O₂ status (188). SARS-CoV-2 uses angiotensin-converting enzyme 2 (ACE2) as a receptor to attach the cellular membrane and enter the intracellular milieu. ACE2 is suppressed by SARS-CoV-2 upon cellular entry, and the activity of VEGF is inhibited by ACE2. The outcome of these inter-inhibitory effects is the high VEGF activity and acute lung injury (187).

Abnormal vasculature leads tumors toward metastasis. Metastasis is a main cause of cancer-related death, which accounts for over 90% of deaths from cancer (189). Abnormal tumor vasculature hampers effective infiltration of CD8⁺ T cells into the tumor area. Normalization of tumor vessels by strategies, such as M1 polarization (121), causes more infiltration of CD8⁺ T cells, thereby hampering immune escape and tumor metastasis (190). FASL expressed in tumor endothelial cells (ECs) is a barrier for CD8⁺ T-cell infiltration into the tumor area (186).

The expression of VEGF is upregulated in hypoxic conditions, and its upregulation reduces immune effector function. VEGF impedes DC maturation, thus causing CD8⁺ T-cell inactivation. VEGF induces PD-1 expression on CD8⁺ T cells and PD-L1 upregulation in the microenvironment of tumors like glioblastoma, thereby causing CD8⁺ T-cell exhaustion (191). VEGF-D is another cytokine in the VEGF family. VEGF-D contributes to the formation of lymphatic vessels (186). Upregulation of VEFG-D contributes to severe SARS-CoV-2-induced diseases (192). High VEGF-D expression is negatively related to the survival of patients with metastatic CRC (193). There is no direct evidence for the possible relation between VEGF-D with CD8⁺ T-cell activity in SARS-CoV-2 cancer patients, which requires focus in future studies.

High VEGF activity is presumably related to the CD8⁺ T-cell dysfunction in patients with a SARS-CoV-2-induced disease and cancer.

CD8⁺ T cells are without a doubt one of the most important cells of the immune system to act against SARS-CoV-2-induced disease and cancer, so their fraction and function are affected by a number of strategies for suppressing tumor development or vaccines against SARS-CoV-2. Evaluation of the fraction and functionality of these critical cells within circulation can, thus, be of prognostic, diagnostic, and therapeutic importance. The aim of new immunotherapeutic strategies is to target co-inhibitory receptors on T cells or improve their tumor recognition abilities and responses against tumor-specific antigens. In fact, responses to immunotherapy are evolved when T cells are directed more toward tumor neoantigens. Peptide-based vaccines are examples in this context. Short peptides directly bind to the HLA-I molecules and act as mounting MHC-I-restricted antigen-specific responses from CD8⁺ T cells. Long synthetic peptides must be presented by APCs to represent a T-cell response. Long peptide vaccination usually causes higher immunity compared with short peptides and induces responses from both CD4⁺ T-helper and CD8⁺ cytotoxic T cells when they are conjugated with effective adjuvant (194). T-cell expansion and strengthening of their antitumor reactivity are achieved after systemic administration of tumor-associated antigens (TAAs). Such approach is effective in patients receiving adoptive T-cell transfer (ACT) (195). The efficacy of antitumor T cells in patients receiving T-cell therapy can also be improved through improving T-cell stemness (196). CD8⁺ T cells in the TME are under exposure to hypoxic conditions, which poses a strong negative impact on their effector function. Thus, a suggested strategy is to modify HIF expression, HIF-2α in particular, in such cells in order to strengthen the adaptation of transferred T cells to the hypoxic conditions of such milieu (197). Outcomes of a recent study showed a positive link between breast cancer exposure to carcinogens with increased infiltration and strengthened antitumor activity of CD8⁺ T cells. Mice upon exposure to the 12-dimethylbenz[a]anthracene (DMBA) carcinogen showed cancer cell upregulation of chemokine (C–C motif) ligand 21 (CCL21) and strengthened antigen presentation activity. CCL21 activity was associated with higher tumor mutational burden (TMB) as well as strengthened T-cell immunity. CD8⁺ T cells were diminished after deletion of the CCL21 receptor, an outcome of which was severe liver and lung metastasis. The results of this study are indicative of the link between carcinogen exposure with stimulation of immune activating factors in cancer cells for potentiating the activity of CD8⁺ T cells against tumor metastasis (198). Cytokine-based therapy using agonists of the TNF receptor family has shown promising antitumor effects, mediated through strengthening the activity of CD8⁺ T cells. An example in this context is the CD137 agonist which shows antitumor activity against gastric cancer (199). Long-lasting responses from T cells can also be elicited using vaccine-based vectors. Cytomegalovirus, for instance, can be used as a vaccine vector for tumor-specific responses from CD8⁺ T cells (200). Strategies can also be expanded through strengthening the intra-tumoral infiltration of CD8⁺ T cells, as is known that cancer cells have developed several mechanisms to diminish homing of T cells and their access to the tumor tissue (201). Reshaping metabolic systems in CD8⁺ T cells is important for boosting their function in the TME that is generally under consistent nutrient and O₂ deprivation. Strengthening fatty acid catabolism is a strategy to improve the antitumor capacity of CD8⁺ TILs. Such metabolically modified T cells presumably show higher antitumor potentials in patients receiving ICI therapy, such as PD-1 inhibitor drugs (202).

Strengthening CD8⁺ T-cell activity is not only effective for cancer but also promising against SARS-CoV-2-induced diseases. SARS-CoV-2 infection triggers cellular immune responses through CD8 overexpression and CTL hyperactivation (203). CD8⁺ T-cell responses are reported to be stimulated using SARS-CoV-2 vaccine boosters (204), and SARS-CoV-2 mRNA vaccines cause fast and stable mobilization of such cells (205). SARS-CoV-2-specific cellular and humoral responses to the inactivated virus vaccine CoronaVac immunization have also been attested (206).