Adaptive immune cells

CD8+ T cells : CD8+ T cells are powerful effector cells in the anti-tumor immune response. CD8+ T cells can specifically recognize cancer cells by binding with their T cell receptor (TCR) to MHC-peptide complexes expressed by cancer cells. Upon TCR engagement, CD8+ T cells destroy target cells through granzyme and perforin-mediated apoptosis or via FASL-FAS-mediated cell death. In tumors, many different CD8+ T cell states can be found. Often, intratumoral CD8+ T cells have a dysfunctional or exhausted phenotype. Immune checkpoint blockade aims to unleash CD8+ T cell responses against cancer.Philip and Schietinger.

CD4+ T cells : CD4+ helper T cells influence a variety of other immune cells; in particular, they contribute to effective CD8+ T cell responses. In cancer, CD4+ T cells play a dual role. In particular, the Th1 subtype of CD4+ T cells exerts anti-tumorigenic functions by providing help to anti-tumor cytotoxic CD8+ cells and B cells and by direct killing of cancer cells via the production of interferon γ (IFNγ) and TNF-α. On the other hand, the Th2 subtype secretes anti-inflammatory mediators that exert pro-tumoral functions. There is growing evidence that CD4+ T cells may play important roles in efficacy of immune checkpoint blockade (ICB).DeNardo et al.

Tregs : Regulatory T cells (Tregs) are a highly immunosuppressive subset of CD4+ T cells and function as gatekeepers of immune homeostasis. Tregs can be subdivided into thymic-derived and peripherally induced Tregs. In cancer, Tregs suppress effective anti-tumor immunity through different mechanisms. Their exact effector program is dependent on context-dependent cues. Treg-targeted cancer therapies are under investigation but are challenging given the key role of Tregs in preventing autoimmunity.

B cells : B lymphocytes are key mediators of humoral immunity. In cancer, B cells can exert anti-tumor effects through antibody-dependent cell cytotoxicity and complement activation. B cells can reside in intratumoral tertiary lymphoid structures (TLSs), where they contribute to T cell activation via antigen presentation. B cells can also support tumor growth by promoting inflammation and immunosuppression via secretion of anti-inflammatory and pro-angiogenic mediators, via immune-complexes, and via complement activation. A subpopulation of immunosuppressive B cells, Bregs, are involved in immunological tolerance.Yuen et al.

Myeloid immune cells

Macrophages : Tumor-associated macrophages (TAMs) represent a highly plastic immune cell population with both pro- and anti-tumorigenic functions. TAMs comprise multiple subsets that arise from different origins (yolk sac-derived tissue-resident macrophages or bone marrow-derived infiltrating macrophages). Moreover, multiple TAM subsets co-exist in tumors. Pro-tumorigenic functions of TAMs include promoting angiogenesis, immunosuppression, metastasis formation, and therapy resistance, while TAMs can also counteract cancer progression by direct phagocytosis of cancer cells or activation of anti-tumor immune responses.

Neutrophils : Neutrophils are the most abundant immune cells in blood. Besides their recruitment to primary tumors, neutrophils frequently accumulate in blood and distant organs of tumor-bearing hosts. Depending on cues from the TME and their maturation status, neutrophils can exert anti- or pro-tumorigenic functions. Their systemic accumulation contributes to immunosuppression and extracellular matrix (ECM) remodeling in distant organs, which promote (pre)metastatic niche formation. Neutrophil diversity and plasticity in cancer is a topic of intense investigation.

Monocytes : Monocytes circulate in the bloodstream and migrate into tissues where they differentiate into macrophages and dendritic cells (DCs). Several subtypes of monocytes exist, including classical, non-classical, and intermediate monocytes. Recent single-cell RNA sequencing studies demonstrated additional monocyte subpopulations. In cancer, monocytes exert pro- and anti-tumoral functions. Monocytes can produce tumoricidal mediators and stimulate natural killer (NK) cells. However, in the TME, they contribute to immunosuppression, ECM remodeling, angiogenesis, and cancer cell intravasation. Moreover, they differentiate into tumor-supporting TAMs.

DCs : DCs are a diverse group of antigen-presenting cells critical for initiating and regulating adaptive immune responses. By integrating information from the TME and relaying it to other immune cells, most notably T cells, DCs have the potential to shape anti-tumor immunity. However, tumors, in turn, employ a variety of strategies to limit and manipulate DC activity to evade immune control. Harnessing the power of DCs to improve immunotherapy response and the development of DC-based vaccines is an active field of cancer research.

Mast cells : Mast cells are granulocytes that mediate host defense and maintenance of homeostasis by swiftly degranulating histamines, cytokines, and chemokines. They are well known for their role in allergies and autoimmunity, but they can also infiltrate tumors. Mast cells exert both pro- and anti-tumorigenic activities depending on the microenvironmental stimuli. They can directly target tumor cells, but they mainly regulate the recruitment and activity of other immune populations and the endothelium.

Eosinophils : Eosinophils are known for their role in allergic diseases and parasite infections. More recently, their function in the TME is becoming apparent. Eosinophils have the capacity to directly kill tumor cells via the release of cytotoxic molecules, but eosinophils can also modulate the tumor vasculature and regulate the immune composition of the TME, and as such, they can have both pro- and anti-tumorigenic functions depending on the activation signals they receive. In addition, there is a growing interest in the role of eosinophils in promoting immunotherapy response.

Myeloid-derived suppressor cells : Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of myeloid cells, consisting of (immature) monocytic and neutrophilic cells with potent immunosuppressive capacities. These cells expand in patients with cancer and mouse cancer tumor models, and their presence in the TME is associated with poor clinical outcome. MDSCs suppress T cells, NK cells, B cells, and DCs via paracrine and cell-cell contact mechanisms.

Platelets : Platelets, also named thrombocytes, are fragments of cytoplasm derived from megakaryocytes in the bone marrow. Platelets lack a nucleus, are abundant in blood, and are essential for blood clotting. Platelets promote tumor progression and metastasis through a range of different mechanisms. They bind to circulating tumor cells (CTCs), promoting CTC survival by shielding them from physical stress and immune attack. Platelets also release pro- and anti-angiogenic mediators, and they bind to endothelial cells, through which they modulate angiogenesis and vascular integrity. Platelets contribute to tumor-associated inflammation and immune evasion by activating myeloid cells.

NK cells : NK cells are cytotoxic innate lymphoid cells. They recognize and kill stressed cells that lack MHC class I expression. Circulating and intratumoral NK cell levels are predictive for improved survival in patients with cancer. NK cells have potent anti-cancer abilities; however, progressing tumors evade elimination by NK cells via several mechanisms, such as the upregulation of inhibitory receptors that diminish NK cell cytotoxicity and the mobilization of immunosuppressive myeloid cells and Tregs. There is a growing interest in utilizing NK cells in the next generation of immunotherapeutic modalities either by engaging endogenous NK cells or by NK cell-based cellular therapies.

Invariant NK T cellsIn : variant NK T (iNKT) cells are CD1d-restricted lipid-specific T lymphocytes that bridge innate and adaptive immunity and can mediate a plethora of immune functions depending on tissue distribution. In several experimental models, iNKT cells exert cancer immunosurveillance through direct tumor cell killing or by orchestrating the activity of both pro- or anti-tumorigenic immune cells. Cancer-associated immunosuppression can skew iNKT cell activity toward more regulatory functions.

Gamma delta T cells : Gamma delta (γδ) T cells form an unconventional T cell population expressing yδ TCRs, but not αβ TCRs, that recognize target antigens in an MHC-independent manner. Depending on the subset, yδ T cells exert effector or regulatory functions. In cancer, yδ T cells may promote disease progression by suppressing anti-tumor immune responses via the production of cytokines, including IL-17. Anti-tumor immunity can also be induced by yδ T cells via direct cytotoxicity mediated by TCR- or NK-receptor interactions or production of effector molecules.

Innate-like lymphocytes : Innate-like lymphocytes (ILCs) are a highly diverse group of immune cells that reside in tissues and that function at the intersection of adaptive and innate immunity. Besides NK cells, ILCs include ILC1s, ILC2s, and ILC3s. ILCs lack antigen-specific receptors and exert their immunoregulatory functions through secretion of a diverse array of cytokines and other inflammatory mediators. In cancer, ILCs play opposing roles. Depending on the tumor types and on cues from the TME, a different composition and activation phenotype of ILC subsets can be found in human tumors. Our understanding of the roles of the different ILCs subtypes in cancer is still very limited.