Cancer Immunology

CANCER IMMUNOBIOLOGY

Gabriela Soriano Hobbs

Alexander M. Lesokhin

Cancer Immunology Basics

The immune system plays an important role in CA surveillance; Rx that modulate & amplify the immune system are referred to as immunotherapies
Innate immunity: 1st line of defense, include Mφ, DC & NK cells, express pattern recognition receptors (eg, toll-like receptors) that recognize conserved molecular patterns on microbes; recognition via these receptors leads to cytokine production, recruitment & activation of additional immune cells, resulting in killing of pathogens; microbial & cellular fragments are then produced & taken up by Ag-presenting cells (Mφ, B-cells, & DC), ultimately activating the adaptive immune system
Adaptive immunity: Generates lifelong immune “memory” → consists of T & B cells, w/c lead to cellular & humoral immunity, respectively; their activation occurs via TCR & BCR that are highly diverse & specific

T Cells

Thymus-derived lymphocytes, recognize Ag complexed w/MHC

Cell

Activated by

Effect

Cytokines Produced

CD4+ (eg helper T cell)

MHC class II (HLA DR) on APC (DC, Mφ)

Regulate either Th1, Th2, Th17, Treg

Th1-IFN-γ, IL-2

Th2-IL-4, IL-5, IL-10

Th17—IL-17, IL23

CD8+ (CTL)

MHC class I (HLA-A, B, C) on all cell types

Once active can directly kill cells

IFN-γ, IL-2, granzyme, perforin

CD4+ cells: Regulate the immune response, activate Th1, Th2, Th17, or Treg responses depending on cytokine milieu when they see Ag on class II MHC; can also activate Mφ & NK cells, w/c mediate effector functions of T cell subsets → IL-2 regulates their proliferation & activation role in tumor immunology; both preclinical models & pts w/↓CD4 function (ie, HIV pts) show ↑ rates of malignancies
Th1 response: (Cellular immune response), activate CTL & Mφ
- Cytokines—activated by IFN-γ, inhibited by IL-10 & IL-4
- CTLs play an important role in detecting virus-infected cells & recognition of tumor cells (tumors frequently express MHC class I, however tumors can also downregulate MHC class I expression & evade CTLs)
Th2 response: (Humoral immune response) leads to B-cell activation, Ab class switching & Ab production, & activation of eosinophils
- Cytokines—activated by IL4 & IL-10. Inhibited by INF-γ.
Th17 cells—activated by IL-1, TGF-β, & IL-6, produce IL-17; found in a variety of malignancies & a/w both pro- & antitumor effects (Am J Pathol 2013;182(1):1-10)
Treg—maintain self-tolerance by suppressing expansion of cells directed against self-Ag; Tregs may also play a role in inhibiting tumor-reactive cells (JCO 2006;24:5373-5380); Tregs are activated in the same milieu as effector cells & specific subsets develop to suppress specific arms of immunity based on environmental cues (Science 2009;326(5955):986-991)
- Type 1 Tregs are activated by IL-10 then produce further IL-10 & TGF-β (Clin Cancer Res 2008;14(12):3706-3715)

Natural Killer (NK) Cells

Part of innate immune response. NK cells express inhibitory & activating KIRs that mediate NK function & play an important role in preventing relapse after allogeneic transplantation in AML (NEJM 2012;367:805-816); NK cells express Fc receptors & play a role in mediating ADCC
Cytokines: Produce INF-γ, activated by IL-2

B Cells

Part of adaptive immune system, produce Ab & serve as APCs
Role of Ab: (1) Activate C′-mediated cytotoxicity via Fc portion of Ab, (2) ADCC, (3) interact w/cell surface receptors that regulate cell growth (egs of this in CA Rx include rituximab, the anti-CD20 monoclonal Ab)

Dendritic Cells (DC)

Stimulated by microbes via pattern recognition receptors, cytokines and/or T-cell signals → they then differentiate & migrate to different tissues & become active APCs
Very effective APC; as such, many tumor vaccines under investigation use DC to deliver tumor Ag
Two main types (though others exist)
- CD11c positive-myeloid DC: Respond to GM-CSF, & are the most efficient APCs, esp for activation of naïve T cells & play a role in activating tumor-specific CTLs via IL-12
- CD11c negative-plasmacytoid DC: Express IL-3 receptor, circulate in the peripheral blood & help mediate innate immune responses, particularly against viruses

Macrophages

Derived from monocytes, specialized phagocytes, function as APCs, recognize cell surface receptors for C′, & Fc receptors for immunoglobin, thus can mediate Ab-dependent cellular uptake
Two main activation states, M1 & M2
- M1: Produce NO synthase, IL-12 & TNF; kill tumor via NO & TNF, a/w improved outcomes in oncology pts (Eur Respir J 2009;33:118-126)
- M2: Produce arginase, IL-10, TGF-β, prostaglandin E2; promote angiogenesis, limit the Th1 response & help tumor growth

Immune Surveillance and Immunoediting

Immunodeficiency is a/w malignancy, as seen in organ transplant recipients, HIV pts, pts w/rheumatic diseases & pts treated w/immunosuppressants; this supports the role of the immune system in CA prev
The three E’s of CA immunoediting: Explanation for the immune system’s role in CA elimination & growth (Review: Nat Immunol 2002;3(11):991-998)
- Elimination—the innate immune system (NK & Mφ) is activated by inflammatory cytokines (produced by tumors); innate system activation leads to ↑ secretion of inflammatory cytokines (IL-2 & INF-γ), activating DCs & Mφ resulting in Ag presentation, T-cell activation (both CD4+ & CD8+) & production of CTLs leading to cell death & eradication of developing tumors
- Equilibrium—elimination of tumor cells leads to selection of less immunogenic cells; this period of selection & elimination can lead to transient control of tumor growth
- Escape—tumors escape the immune system via loss of molecules on tumor cells important for immune activation; tumors can secrete immunosuppressing cytokines (IL-10 & TGF-β) & downregulate INF-γ; in addition, tumors often express non-mutated self-Ag, w/c the immune system will, by definition, not react against; tumors can express molecules that inhibit T-cell function, eg, PD-L1/B7-H1, w/c binds an inhibitory receptor on T cells (PD1) & leads to their inhibition (Immunology 2007;450(7171):903-907)
Tumor microenvironment—immune cells are found in tumors, the exact composition of these cells has been a/w pt outcomes; eg, high concentration of tumor-infiltrating lymphocytes (CD8+ cells) are a/w better outcomes & ↑ response to chemotherapy, Tregs & myeloid-derived suppressor cells are a/w worse outcomes, the exact role of Th17 in tumors is still being elucidated; the milieu of cytokines & chemokines also plays a role in outcome; some cytokines (VEGF, IL-1, IL-8) lead to endothelial cell proliferation, migration, & activation; tumor associated Mφ help promote tumor cell invasion & mets (Nat Rev Cancer 2012;12(4):298-306, Immunology 2011;121(1):1-14)